The Importance of Synthetic Drugs for Type 2 Diabetes Drug Discovery

Review The importance of synthetic drugs for type 2 diabetes drug discovery

† Maliheh Safavi, Alireza Foroumadi & Mohammad Abdollahi † 1. Introduction Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran, Iran 2. Pathophysiology of T2DM 3. Overview of current synthetic Introduction: Type 2 diabetes mellitus (T2DM) is a major metabolic, drugs in the treatment of multi-causal and heterogeneous disorder which causes significant morbid- T2DM ity and mortality with considerable burden to healthcare resources. The 4. New synthetic compounds as number of deaths due to T2DM highlights the insufficiency of the cur- DPP-4 inhibitors rently available drugs for controlling the disease and its complications and more needs to be done. 5. New synthetic compounds as Areas covered: SGLT2 inhibitors This paper reviews the updated pathobiology of T2DM that should be targeted in drug discovery. Further, the article provides discussion 7. Conclusion on the mechanism of action, side effects and structure of the currently avail- 8. Expert opinion able synthetic drugs. The authors specifically evaluate two newer classes of anti-diabetic agents: dipeptidyl peptidase IV (DPP-4) and sodium-glucose transporter-2 (SGLT2). They also present information on newer synthetic compounds. The article also highlights the key interactions between synthetic compounds and DPP-4 active site residues for rational drug design. Expert opinion: Numerous anti-hyperglycaemic drugs are currently available but many are limited by their adverse effects. The identification of the 3D structure of DPP-4 has opened new avenues for design, thus aiming to pro- duce drugs that directly exploit the structural characteristics of this binding site. Further, structural- and ligand-based screening techniques have been developed for designing novel DPP-4 and SGLT2 inhibitors. There has also

For personal use only. been progress with the design and development of novel T2DM therapeutics including: PPARa/ dual agonists, Sirtuin 1 activators, glycogen phosphorylase inhibitors and protein tyrosine phosphatase 1B inhibitors. Finding new targets and synthesis methods is still essential but it is becoming accepted that no diabetic therapy is ‘best suited’ with each patient responding differently.

Keywords: anti-diabetic agents, dipeptidyl peptidase IV inhibitors, sodium-glucose transporter- 2 inhibitors, synthetic drugs, type 2 diabetes

Expert Opin. Drug Discov. (2013) 8(11):1339-1363

1. Introduction Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13

Diabetes comprises a group of metabolic disorders characterised by chronic hyperglycaemia with disorders in the metabolism of carbohydrate, fat and protein that result in defects in secretion and action of insulin [1]. Dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and the blood vessels are the usual complications of diabetes [2,3]. Diabetes is mainly divided into four main types including insulin-dependent diabetes mellitus (type 1), non-insulin-dependent diabetes mellitus (type 2), gestational diabetes and other specific types [1,4]. Type 2 diabetes mellitus (T2DM) is very common and accounts for ~ 90 -- 95% of all diabetic cases. The worldwide increase in T2DM becomes a most important health concern [5]. T2DM is usually accompanied with insulin resistance in the skeletal muscles and the liver, and the reduction in insulin production by the pancreas [6]. Genetic susceptibility and various environmental factors [7,8] are also involved in T2DM. Patients with T2DM are at risk of vascular complications

have not yet been clearly elucidated. For instance, unlike Article highlights. type 1 diabetes, autoimmune destruction of cells does not . The incidence of T2DM continues to grow rapidly occur and ketoacidosis seldom occurs [33]. As mentioned ear- worldwide and is associated with multiple comorbidities. lier, peripheral insulin resistance and b-cell dysfunction are . Peripheral insulin resistance and b-cell failure represent rather involved in T2DM [34]. Insulin resistance and the the core pathophysiological defects in T2DM. related consequences called insulin resistance syndrome . Currently available synthetic drug therapies include metformin, sulphonylurea and other insulin (IRS) or the metabolic syndrome are common in T2DM, secretagogues, thiazolidinediones, a-glucosidase deemed mainly linking to patients’ genetic background [35]. inhibitors, GLP1 agonists, dopamine-2 agonists, bile acid Insulin resistance is also linked to obesity [36], dyslipidemia, sequestrants, DPP-4 and SGLT2 inhibitors. hypertension and increased cardiovascular risk [37]. . Two latter classes (DPP-4 and SGLT2 inhibitors) are novel However, risk alleles in some loci seem having a primary and promising drugs that target novel mechanisms. . Finding new drug targets and new faster and cheaper impact on insulin sensitivity. Peroxisome proliferator- synthesis methods are the main goals of T2DM activated receptor-g (PPAR-g), glucokinase regulator and drug discovery. insulin-like growth factor 1 have been proved as insulin resistance locus from T2DM susceptibility loci [38]. Obesity and This box summarises key points contained in the article. lifestyle are independent risk factor for T2DM [1,39]. Accord- ing to short-term studies, numerous benefits of weight loss can be achieved in overweight or obese patients with such as coronary artery disease, stroke, hypertension, T2DM. The finding of recent study indicated that the inten- nephropathy, peripheral vascular disease, neuropathy and sive lifestyle intervention do not reduce the rate of cardiovas- retinopathy [9-13]. It has been suggested that higher glucose cular morbidity and mortality in overweight or obese patients levels may be a risk factor for dementia [14]. Although with T2DM [40]. Gastric bypass induces substantial and sus- T2DM was traditionally seen in individuals over the age of tained weight loss and is a highly effective treatment for 40, recent data from several countries confirm that T2DM obesity-related diabetes. Laboratory data suggest that gastric occurs in younger people even in childhood [15,16]. Cases of bypass exhibits reprogramming of intestinal glucose metabo- T2DM that occurs before 30 years of age usually develop dia- lism which renders the intestine a major tissue for glucose dis- betic nephropathy, renal failure, blindness and atherosclerotic posal, contributing to the improvement in glycaemic control vascular disease in their 30s [17]. after surgery [41]. Although there are several therapeutic options available for Several studies have indicated that obesity correlates with a

For personal use only. the management of diabetes, most of them respond only in low-grade inflammation of the white adipose tissue. This the short-to-medium term. Further, most of current therapies results from activation of some pro-inflammatory signalling are associated with an increased risk of adverse effects such as pathways which end up with insulin resistance, impaired glu- weight gain (sulphonylureas, thiazolidinediones and insulin), cose tolerance and diabetes [39,42]. Recent data indicate that hypoglycaemia (sulphonylureas and insulin), gastrointestinal white adipose tissue in obese patients is infiltrated by macro- intolerance (metformin) and myocardial infarction (rosiglita- phages [43]. Several pro-inflammatory factors, such as zone) [18,19]. Researchers are trying to find therapies better TNF-a and IL-6, are derived not only from adipocytes but than the three oldest classes, for example, insulin, sulphonylur- also from infiltrated macrophages [39]. The role of cytokines eas and biguanides but the newer ones have not shown more and insulin signalling pathways should not be missed as this potency and were often less effective in lowering glycaemia [19]. interaction results in change of insulin action [44,45]. Nor- Alternative to these synthetic agents, new insulin analogues, mally, insulin acts through binding to and activation of its inhaled insulin and many medicinal plants are being investi- cell-surface receptors. Such receptors are made up of two a Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 gated for possible benefits in diabetes [20-30]. Moreover, insu- subunits and two b subunits, which are disulfide linked lin-- mimetic complexes have been synthesized in the thought into a2b2 heterotetrameric complex. The actions of insulin that these complexes affect both diabetes and its complica- are initiated when the receptor is bound to the extracellular tions [31,32]. Of course, concerns of safety and tolerability of a subunits, causing phosphorylation of intracellular tyrosine current treatments and the progressive nature of T2DM call kinase domain of the b subunits and inducing a con- for new classes of medicines. This review provides a discussion formational change [46-48]. Phosphorylation of the insulin of current synthetic pharmacological agents and new synthetic receptor can activate insulin receptor substrate complexes compounds for T2DM. (IRS-1 -- IRS-4). The activated IRS binds to the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase that results 2. Pathophysiology of T2DM in activation of p110 catalytic subunit [47,49,50]. PI(3,4,5) P3 which is produced by enzymatic activity of PI3-kinase is Unlike simple characterisation of type 1 diabetes, the patho- a key lipid second messenger in various metabolic effects of genesis of T2DM is more complex and still remains a matter insulin [51]. PI (3,4,5)P3 mediates the signal transduction to of argument. The most problem is that the specific aetiologies downstream molecules including Akt and atypical protein

1340 Expert Opin. Drug Discov. (2013) 8(11) Importance of synthetic drugs for T2DM drug discovery

Obesity & life style Genes

Insulin Thiazolidinediones resistance biguanides

Sulphonylureas β cell non- dysfunction sulphonylureas (decreased insulin GLP-1 analogs Impaired secretion) DPP4 inhibitors glucose tolerance Decreased glucose Sulphonylureas transport (muscle and adipose tissue)

Increased Type 2 hepatic glucose Biguanides diabete production mellitus

Figure 1. Pathobiology and targets for current drugs in T2DM.

kinase C. These are the key signalling molecules in the activa- ends up in b-cell exhaustion and finally b-cell failure and

For personal use only. tion of glucose uptake, inhibition of apoptosis and synthesis diabetes [60]. of proteins [49,52-54]. Numerous studies have demonstrated that enhanced pro- It is thought that in adipose and retinal tissues, phosphory- inflammatory cytokines, free radicals and oxidative stress are cen- lation on specific serine sites (Ser307) on IRS-1 reduces tral events to the development of diabetic complications [13,64-66]. the tyrosine phosphorylation of the insulin receptor [48,55]. Dominant cause of oxidative stress in diabetes is glucose autoxi- The cytokine TNF-a plays a major role through phosphory- dation that leads to production of free radicals [67]. Oxidative lation of the IRS-1 protein on Ser307 site. TNF-a-induced stress causes b-cell death via induction of mitochondrial stress inhibition of IRS-1 signalling can reduce Akt phosphorylation during development of diabetes. In pancreatic b cells, important and stop the insulin signalling pathway [39,48]. Also, it has targetsforanoxidantinsultareATP-dependentpotassium been shown that TNF-a causes marked downregulation of (KATP) channels and cell metabolism [68]. The efficacies of dif- the adipocytes and muscle cells insulin-regulable glucose ferent approaches in the reduction of diabetes-induced oxidative transporter [56]. stress have been studied and usage of antioxidants as the Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 According to recent studies, the circulating IL-6 correlates supplement to drug regimen of T2DM patients has been with insulin sensitivity in obese humans [57]. This means recommended [69-79]. Briefly, the pathobiology of T2DM which that both TNF- a and IL-6 and other adipocyte-specific sig- are considered as targets for classic and current synthetic drugs nalling elements such as resistin and leptin can alter insulin are summarised in Figure 1. sensitivity by provoking diverse key steps in the process of insulin action [36,58]. Any defect in insulin action or the IRS 3. Overview of current synthetic drugs in the triggers b-cells in a way to cause T2DM [59]. The interplay treatment of T2DM between insulin resistance and b-cell dysfunction remains highly complex [60]. Studies of insulin-resistant animals illus- 3.1 Biguanides trate an important role for expansion of the b-cell mass and The class of biguanides includes the metformin and two with- enhanced b-cell function as the compensatory mecha- drawn agents phenformin and buformin. The reason for nisms [61]. In most obese and insulin-resistant individuals, removing phenformin and buformin from the market was b-cell compensation reduces due to hyperglycaemia and lipid the occurrence of fatal lactic acidosis [80,81]. Introduced in toxicity [62,63]. Continuous decline of b-cell function usually the market in 1950, metformin is a well-accepted first-line

Expert Opin. Drug Discov. (2013) 8(11) 1341 M. Safavi et al.

choice for the treatment of T2DM due to its good efficacy, sulphonylureas and appears to have several clinical advan- low price and low rate of adverse effects especially in long-term tages over conventional sulphonylureas [108]. In clinical stud- use [82-85]. Metformin reduces fasting plasma glucose concentra- ies, glimepiride provides more stable blood glucose control, tions by reducing rates of hepatic glucose production through lowers risk of hypoglycaemia and induces less weight gain in a reduction in gluconeogenesis and glycogenolysis [86-88]. comparison to other sulphonylureas [108,109]. Owing to glime- Metformin also affects peripherally and improves skeletal myo- piride pancreatic tissue specificity, its use may be safer in cyte glucose uptake, reduces the overall plasma free fatty acid patients with cardiovascular disease. Cardiovascular side effects (FFA) concentration and induces mild weight loss through of these compounds result from their effect on KATP channels reduction of caloric intake [89,90]. present in extra-pancreatic tissues of the cardiac and vascular Activation of adenosine monophosphate-activated protein smooth muscle [110,111]. kinase (AMPK) is required for metformin’s inhibitory effects All sulphonylureas contain a central S-phenyl sulphony- on glucose production by hepatocytes and acetyl-CoA carbox- lurea structure (red highlight in the glimepiride structure in ylase activity and its inducing effects on glucose uptake by the Table 1) [107]. The pharmacokinetic and pharmacological skeletal muscles and fatty acid oxidation. It should be noticed differences among the available sulphonylureas are a conse- that AMPK is a major cellular regulator of lipid and glucose quence of substitutions at the para-position on the benzene metabolism [91,92]. Metformin, by improving insulin sensitiv- ring and the other at a nitrogen residue in the urea moiety [112]. ity, also improves a variety of other factors related to increased First-generation sulphonylureas (e.g., tolbutamide, acetohexa- cardiovascular risk. It reduces the rate of myocardial infarc- mide, tolazamide and chlorpropamide) have relatively small, tion and all-cause mortality [93]. However, gastrointestinal polar, hydrophilic substitutions. Second-generation sulphony- intolerance, such as nausea, abdominal pain and diarrhoea, lureas have large, non-polar, lipophilic substitutions that happens as a side effect in about 30% of the users that limits penetrate cell membranes more easily, giving them greater the compliance of patients to consume top effective potency [107,112]. doses [94,95]. Although rare, fatal lactic acidosis might be observed in some users [96,97] and thus it should not be used in patients with liver disease [95], renal dysfunction [97] and 3.3 N=lurea insulin secretagogues in those with a slight degree of creatinine elevation [98]. The Anti-diabetic and insulinotropic properties of the non- structure of biguanide (red highlight in metformin structure sulphonylurea moiety of glibenclamide, subsequently named in Table 1) is conventionally represented in a wrong tauto- meglitinide, have been discovered > 30 years ago. Repagli- meric form which was corrected in 2005 [99]. They are moder- nide, nateglinide and mitiglinide are proposed as non-

For personal use only. ately strong bases and form HCl salts quite readily. This aspect sulphonylurea insulinotropic agents exhibiting structural is being exploited in the preparation of oral formulations of analogy with meglitinide [113,114]. Repaglinide and nategli- metformin with desired properties [99,100]. nide have been approved for treatment of T2DM and have been released into market in 1998 and 2001, respec- 3.2 Sulphonylureas tively [115]. Repaglinide and nateglinide have a mechanism Sulphonylureas as the fast insulin secretagogues are the oldest of action that is similar to that of sulphonylureas [104]. available class of oral glucose-lowering agents which were They are short-acting insulin secretagogues with high introduced in the market in the 1940s and approved for use affinity and rapid association-- dissociation kinetic activity in 1994 for T2DM before metformin [85,95,101]. to the KATP at the outer membrane of b-cells. This property These drugs specially stimulate insulin secretion in a of these compounds results in restoration of early phase glucose-independent manner by binding to a regulatory pro- insulin secretion [107,113]. The most common adverse events tein called sulphonylureas receptor on the pancreatic b-cells. of repaglinide and nateglinide are upper respiratory tract Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 After binding to the receptors, they trigger closure to KATP infection, sinusitis, constipation, arthralgia, headache and channels, membrane depolarisation and influx of calcium vomiting [116]. through voltage-dependent channels, which subsequently Nateglinide is D-phenylalanine derivative (phenylalanine is ends up in insulin secretion [102-104]. In addition to their highlighted as red in the Table 1) which blocks KATP channels pancreatic effects, sulphonylureas can enhance insulin- in the pancreatic b-cells to stimulate insulin release [117,118].In stimulated peripheral glucose utilisation through triggering therapeutic concentrations, nateglinide with no sulphonylurea insulin action on adipose tissue glucose transport and lipogen- or benzamido moiety induces high selectivity for the pancre- esis and skeletal muscle glycogen synthase [105,106]. atic KATP subtype over the cardiovascular subtype [119]. Nate- This class of oral drugs include the second-generation glinide sensitizes pancreatic b-cells to limited amount of agents glipizide, gliclazide, glibornuride, gliquidone, glisoxe- glucose and reduces the glucose concentration needed to stim- pide, glyclopyramide and glibenclamide as well as the ulate insulin secretion [118]. In contrast to other insulin secre- first-generation agents acetohexamide, chlorpropamide, tol- tagogues, nateglinide has a low propensity to cause azamide and tolbutamide [107]. The third-generation sulpho- hypoglycaemia because of its selective, early phase insulin nylurea glimepiride is as effective as second-generation secretion and transient effect [120].

1342 Expert Opin. Drug Discov. (2013) 8(11) Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 For personal use only.

Table 1. Current anti-diabetic synthetic drug classes.

Drug class Drug structure Mechanism of action Side effects Study

Biguanide NH2 NH Reduces hepatic glucose Gastrointestinal complaints Bharatam et al. 2005,

CH3 production, increases and lactic acidosis Lipska et al. 2011 [99,236] N N NH2 peripheral glucose utilisation

CH3 and insulin sensitivity Metformin Sulphonylureas O Stimulates insulin release Very rare adverse effects Korytkowski 2004, from pancreas and reduces compared to other Becic et al. 2003 [107,237] HN N H post-absorptive rates of sulphonylureas side effects O S O endogenous glucose such as hypoglycaemia and production weight gain xetOi.Du Discov. Drug Opin. Expert O H N N

O Glimepiride Non-sulphonylureas Increases insulin secretion in Mild gastrointestinal Chachin et al. 2003, O H the pancreas complaints and weight gain Campbell 2005 [119,120] NH (2013) motneo ytei rg o 2Mdu discovery drug T2DM for drugs synthetic of Importance HO O

8 Nateglinide (11) Thiazolidinediones O Lowers insulin resistance in Weight gain, fluid retention Yki-Jarvinen 2004, peripheral tissue by and heart failure Defronzo 2009 [125,128] H NH activating PPAR-g N S O O N Rosiglitazone Disaccharidase inhibitors OH Inhibits intestinal a- Gastrointestinal disturbance Balfour et al. 1993, HO glucosidase enzymes such as flatulence, Clissold and Edwards abdominal distension, 1988 [141,238] H C OH HO 3 OH stomach rumble and O N O diarrhoea HO H O HO OH O HO OH O HO OH OH Acarbose 1343 Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 For personal use only. 1344 Safavi M. Table 1. Current anti-diabetic synthetic drug classes (continued).

Drug class Drug structure Mechanism of action Side effects Study tal et GLP1 agonists O Stimulates insulin Nausea and vomiting Wajcberg and Amarah

biosynthesis and secretion, 2010, Madsbad . CH3 NH H inhibits glucagon secretion 2009 [159,239] COOH and slows gastric emptying O

Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Phe Thr Gly Arg Gly Arg Val LeuTrp Ala Ile Gly Glu Ala His xetOi.Du Discov. Drug Opin. Expert Liraglutide DPP-4 inhibitors Inhibits DPP-4 that improves Few gastrointestinal Gupta et al. 2009, N glycaemic control disturbance Panina 2007 [168,240] HN

O N OH

(2013) Vildagliptin SGL2 inhibitors CH3 Inhibits SGLT2 in the kidneys Low incidence of Nomura et al. 2010, S hypoglycaemia and genital Rosenstock et al. 8 F (11) infections in females 2012 [179,241]

OH O HO OH OH Invokana (canagliflozin) Dopamine-2 agonists Resets abnormally elevated Fatigue, nausea, vomiting, Keche 2010, HO H hypothalamic drive for dizziness and headache Kumar et al. O N O N increased plasma glucose, 2012 [181,182] H CH SO H N 3 3 triglyceride and FFA levels O O N

HN Br Bromocriptine Importance of synthetic drugs for T2DM drug discovery

3.4 Thiazolidinediones affecting the breakdown of disaccharides to monosaccharides Troglitazone was the first thiazolidinedione approved as a in the intestinal epithelium. As a consequence, delayed and glucose-lowering therapy for patients with T2DM in decreased absorption of the sugars happen. The a-glucosidase 1997 [98,121]. Troglitazone was subsequently withdrawn from inhibitors decrease both postprandial blood glucose and post- use, in March 2000, because of causing severe hepatic toxic- prandial insulin levels and in that way these improve sensitivity ity [122]. Two currently available PPAR-g agonists, rosiglita- to insulin and release the stress on b-cells [139]. zone and pioglitazone, were approved in 1999. This class of The safety of a-glucosidase inhibitors may be a definite agents also known as glitazones like the biguanide metformin help in elderly patients with T2DM [140]. The efficacy of acar- do not increase insulin secretion but rather increase insulin bose and miglitol is limited by the adverse reactions caused by sensitivity in muscle and adipose tissue and in the liver by a large amount of non-absorbed disaccharides in the intestinal activating PPAR-g and affecting gene regulation in the target tract with the attendant symptoms of abdominal bloating, cells [123-125]. diarrhoea and flatulence. These compounds do not induce PPAR-g is essential for normal metabolism of lipids such as hypoglycaemia or weight gain [139,141]. adipocyte differentiation and proliferation as well as fatty acid According to some studies, acarbose does not directly alter uptake and storage [126,127]. Thiazolidinediones exert their insulin resistance but may lower postprandial plasma insulin insulin-sensitising actions by promoting genesis of small adipo- levels, fasting blood glucose, glycosylated haemoglobin, cytes and redirect fat from non-adipose tissues, such as liver fat, plasma triglycerides and/or cholesterol concentrations [141,142]. to (subcutaneous) adipose depots [125,128]. Although thiazolidi- Acarbose is only minimally absorbed from the gut and thereby nediones may enhance insulin sensitivity by keeping fat where considered as a non-absorbable inhibitor that makes this drug it belongs and sparing other tissues such as the liver, skeletal with no systemic adverse effects even after long-term adminis- muscle and possibly b-cells from lipotoxicity, indirect effects tration. The symptoms, which is due to undigested carbohy- -- may also be involved via alteration of gene transcription such drates, occur in ~ 30 60% of patients and tend to decrease as adiponectin. Adiponectin, an adipocytokine, produced with time and seem to be dose-dependent [142,143]. Acarbose is exclusively by adipose tissue increases insulin sensitivity [129-131]. composed of an acarviosin moiety with a maltose at the reduc- The potential of thiazolidinediones to lower glucose pro- ing terminus. Acarviosin is a sugar composed of cyclohexitol duction by the liver or improve glucose transport into muscle unit linked to a 4-amino-4,6-dideoxy-D-glucopyranose unit, and adipose tissue have been shown [14,132]. The main adverse which is part of the acarbose and its derivatives (highlighted events associated with the thiazolidinediones class are weight as red in the Table 1) [144]. gain and fluid retention that may be severe enough to exacer-

For personal use only. 3.6 bate or precipitate heart failure [133,134]. These drugs also cause Glucagon-like peptide 1 agonists slight decrease in the haemoglobin level and haematocrit, In April 2005, the first glucagon-like peptide 1 (GLP-1) probably without clinical consequence [125]. Pioglitazone and agonist, exenatide, was approved for the treatment of rosiglitazone are licensed for use as the second-line therapy T2DM [145]. In 2010, other analogue liraglutide was approved to metformin and glyburide, agents that have demonstrated for use as an adjunct to diet and exercise to improve glycaemic efficacy in decreasing the microvascular and macrovascular control in adults with T2DM [146]. Several additional complications associated with T2DM [14]. GLP-1 agonists, including exenatide long-acting release [15,147] Thiazolidine-2,4-dione structure (red highlight in the rosi- albiglutide and taspoglutide, are under development and in glitazone structure in the Table 1) is common to all thiazolidi- various stages of clinical trials [148]. nediones [135]. Thiazolidinedione ring has been investigated as GLP-1 is a gut-derived incretin hormone, which is secreted potent polar head group which is a critical binding motif in by the more distally located intestinal L cells. Incretin hormones are a group of gastrointestinal hormones released in

Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 the active site of PPAR ligand-binding domain. However, these polar head groups are prone to racemisation under response to nutrient ingestion, which cause an increase in physiological conditions [136]. the amount of insulin released even before elevation of blood glucose [149]. Incretin hormone, GLP-1 stimulates insulin biosynthesis and secretion in response to meal ingestion, inhibits 3.5 Disaccharidase inhibitors (a-glucosidase glucagon secretion, slows gastric emptying, reduces appetite inhibitors) and promotes the regeneration and proliferation of pancreatic The a-glucosidase inhibitors acarbose and miglitol are two of b-cells [149-151]. these agents which were released in the market in 1996 [95]. Since GLP-1, gastric inhibitory polypeptide (GIP) and glu- Initial investigations of voglibose as another disaccharidase cagon are all pivotal in glucose homeostasis, the G-protein- inhibitor have not been proceeded further [137,138].Absorption coupled receptors represent important drug targets in T2DM. of carbohydrates requires eventual breakdown of disaccharides One novel diabetes treatment strategy is activation of GLP-1 into monosaccharides by the a-glucosidase enzyme in the brush receptors and inhibition of the glucagon signal [152]. The struc- border of the small intestine. Disaccharidase inhibitors, such as ture of the human glucagon class B G-protein-coupled receptor acarbose and miglitol, inhibit digestion of carbohydrates by has been reported more recently. The distinct structural

Expert Opin. Drug Discov. (2013) 8(11) 1345 M. Safavi et al.

features and larger binding pocket of this receptor provide new may also cleave substrate with non-preferred amino acids at insights into the molecular details of peptide ligand binding this position [167]. and a more reliable structural template for the design of specific DPP-4 inhibitors include diverse structural types. Many and potent small molecules for the treatment of T2DM [153]. DPP-4 inhibitors have five-membered heterocyclic rings -- The short half-life (t1/2 ~ 1 1.5 min) of GLP-1, because such as pyrrolidine, cyanopyrrolidine, thiazolidine and cyano- of their rapid inactivation by dipeptidyl peptidase IV thiazolidine as a proline mimetic in the P1 part. Vildagliptin (DPP-4) in the circulation, is a major difficulty for its structure as a cyanopyrrolidine derivatives are presented in use [149,154]. Exenatide is a synthetic form of exendin-4 that the Table 1 (cyanopyrrolidine ring is highlighted in red) [18]. occurs naturally in the saliva of the Gila monster (a large ven- Despite the positive results of vildagliptin in clinical trials, omous lizard native to southwestern United States) and its one of the issues encountered with the use of 2-cyano pyrroli- amino acid sequence shows 53% homology to human dine derivatives is their stability in solution due to the partic- GLP-1 [155]. Exendin-4 and GLP-1 exhibit similar insulino- ipation of cyano group in an intramolecular cyclisation tropic potencies in both in vitro and in vivo models, while process leading to inactive products [168]. exendin-4 has a better efficacy and a longer duration of action However, at this time, the tolerance and safety profile of than the native GLP-1 in rodents and humans [156]. Exenatide DPP-4 inhibitors are considered as excellent. Possible and liraglutide exhibit increased resistance to DPP-4 degrada- increased risk of acute pancreatitis in the short term and tion and thus provide pharmacological levels of GLP-1. Exe- occurrence of chronic pancreatitis in the longer term are natide as short-acting GLP-1 receptor agonists (t1/2 ~ 2.4 h) among concerns attributed to increase in GLP-1 levels. is recommended for twice daily dosing [154]. Nausea, vomiting Non-consistent results regarding a possible effect of GLP-1 and hypoglycaemia were the most frequently reported side and DPP-4 inhibitors on the exocrine pancreas were reported effects and were indifferent to dose while headache and naso- in various animal models [169]. In view of likely toxic side pharyngitis were seen more at lower dose [147]. Liraglutide, but effects associated with the inhibition of other members of not short-acting exenatide, was associated with thyroid DPP family (inhibition of which was linked to toxicity in ani- C-cell hyperplasia and tumours in rodents, probably due to mal studies), it seems necessary to design selective inhibitors continuous high-dose GLP-1 agonist exposure [157]. Rare cases targeting DPP-4 over DPP-8 and DPP-9 [170]. Achieving of acute pancreatitis in association with use of incretin- desired selectivity toward the inhibition of DPP-4 over other based classes have been reported but the most of ensuing related peptidases such as DPP-8 and DPP-9 and long- reports showed inconsistent results [85,158]. Liraglutide is a acting potential for maximal efficacy are the main challenges. long-acting GLP-1 analogue (t1/2 ~ 24 h), with 96% struc-

For personal use only. tural identity to human GLP-1. The addition of a C16 fatty 3.8 Sodium-glucose transporter-2 inhibitors acid side chain using a -glutamic acid spacer at the -amino Canagliflozin from the new class of medications called group of lysine-26 (fatty acid palmitate is highlighted as red sodium-glucose transporter-2 (SGLT2) inhibitors was in the Table 1), which allows non-covalent binding to albu- approved by FDA in March 2013 [171]. Although there are min, increases the stability through formation of heptamer several candidates, SGLT2 inhibitors such as dapagliflozin mediated by the fatty acid side chain [159]. and BI10773 are now in various stages of clinical development, and the phlorizine, sergliflozin and remogliflozin have 3.7 DPP-4 inhibitors been discarded [172]. DPP-4 inhibitors are promising new class of anti-diabetics Kidney plays a key role in glucose homeostasis, primarily that are extremely studied [10]. In October 2006, the first by the reabsorption of filtered glucose especially by the DPP-4 inhibitor, sitagliptin, was introduced in the market. SGLT2 located in the proximal convoluted tubule. SGLT1, Indeed, several other drugs such as vildagliptin, saxagliptin, the other SGLTs isoform, is the key transporter for glucose Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 alogliptin, linagliptin and anagliptin have been approved in absorption in the gastrointestinal tract and plays only a minor certain countries for the treatment of T2DM. Other candi- role in the kidney [173,174]. The expression of SGLT2 and dates have been demonstrated to be in an advanced stage of other renal glucose transporters were elevated in diabetic clinical trials for T2DM [160-163]. patients [175]. SGLT2 inhibitors, with a greater selectivity for Inhibition of DPP-4, a serine protease, enhances endoge- SGLT2 versus SGLT1, offer a considerable advantage as nous GLP-1 activity by decreasing the rate of GLP-1 degrada- potential anti-diabetic medications, because of their ability tion, which represents a promising approach to the treatment to inhibit renal glucose reabsorption and subsequent plasma of T2DM [164]. DPP-4 inhibitors increase circulating glucose-lowering effect without inducing excessive insulin GLP-1 and GIP levels in humans, which leads to increased secretion [172,176]. glucose-dependent secretion of insulin and decreased blood Canagliflozin, an oral selective SGLT2 inhibitor improves glucose, haemoglobin A1C and glucagon levels [165,166]. glycaemic control in T2DM by reducing renal threshold DPP-4 is a 766 residue N-terminal dipeptidyl exopeptidase for glucose reabsorption and increasing the urinary glucose that specifically cleaves an amino acid sequence having proline excretion ending up in weight loss [177]. Various SGLT2 or alanine at the N-terminal penultimate (P1) position but inhibitors have been proposed based on the glucoside

1346 Expert Opin. Drug Discov. (2013) 8(11) Importance of synthetic drugs for T2DM drug discovery

structure (glucoside ring is highlighted in red in canagliflozin the non-peptidomimetic inhibitors include alogliptin and structure in the Table 1). Since, the O-linkage of the structure linagliptin (Figure 3). of SGLT2 inhibitors is a metabolic target for b-glucosidase enzymes that can restrict the activity of SGLT2 inhibitors 4.1 Peptidomimetic inhibitors in vivo, newer candidate with a C-glucoside linkage such as The b-methylphenylalanine-derived amides have been shown canagliflozin have been synthesized [178]. Canagliflozin as a to be potent DPP-4 inhibitors, exhibiting suboptimal selectiv- C-glucoside bearing a heteroaromatic ring has improved ity and pharmacokinetics [187,188]. A series of phenylalanine metabolic stability in comparison to O-glucoside [179]. and cyclohexylalanine derivatives also known as fluorinated pyrrolidine amides [10] were designed and assayed for their 3.9 Bile acid sequestrants/dopamine-2 agonists inhibitory potency against the DPP-4 enzyme as well as their From this category, two classes of drugs were already selectivity over the related proline-specific enzymes quiescent approved for other diseases. Colesevelam hydrochloride is a cell proline dipeptidase (QPP) (DPP-II), DPP-8 and DPP-9. bile acid sequestrant that had been originally approved for The phenylalanine series afforded compounds such as com- the treatment of hypercholesterolaemia in the 2000s and pound (1) that were potent and selective. Among cyclohexyla- approved in January 2008 to improve glycaemic control in lanine derivatives, the acetamide b-methyl substitute (2)was T2DM adults. The exact mechanism influencing glucose the most potent with better oral bioavailability [189]. metabolism remains unexplained [180]. The effect of substitution on the imidazopiperidine- The bromocriptine mesylate, a quick release formulation based b-amino acid derivatives inhibitory activity against by trade name Cycloset, as an adjunct to diet and exercise DPP-4, DPP-8 and DPP-9 was evaluated in another study. has been approved to improve glycaemic control in adults Introduction of a substituent at the 4-position of the imidazo- with T2DM on 2009 [181]. Bromocriptine mesylate is a sym- piperidine unit (3) produces compounds having DPP-4 IC50 patholytic D2 dopamine agonist which can reverse many of values < 10 nM [190]. the metabolic alterations associated with insulin resistance A series of novel azobicyclo[3.3.0] octane derivatives substi- and obesity via resetting dopaminergic and sympathetic tone tuted with pyrrolidine-2-carbonitrile were synthesized and eval- within the central nervous system [182]. uated against DPP-4, DPP-8 and DPP-9. Among them, Clinically, bromocriptine is used in treating Parkinson’s compound (4) exhibited good DPP-4 activity, high selectivity, disease through activity at dopamine receptors and in treating moderate pharmacokinetic profiles and excellent in vivo effi- hyperprolactinaemia and acromegaly. Bromocriptine was cacy in an oral glucose tolerance test (oGTT) in lean mice [191]. used for 30 years for other indications and based on its activity Anagliptin is a potent and highly selective DPP-4 inhibitor

For personal use only. in modulating central glucose and energy metabolism path- which has been approved in Japan for the treatment of ways has been approved for the treatment of T2DM [181,183]. T2DM in 2012 [162,192]. A series of pyrazolo[1,5-a]pyrimidines Bromocriptine is a semisynthetic derivative that is derived were found to be novel DPP-4 inhibitors. Compounds were from a natural ergot alkaloid but bromocriptine mesylate evaluated in vitro for inhibition of human recombinant DPP-4 has been chemically designated as 2-bromoergocryptine and also screened for selectivity over dipeptidyl peptidase monomethanesulfonate (salt) [182]. More information is 8and9.Structure-- activity relationships (SARs) for compounds presented in the Table 1. showed N-[2-(amino)-2-methylpropyl]-2-methylpyrazolo [1,5-a]pyrimidine-6-carboxamide hydrochloride (5) (anagliptin 4. New synthetic compounds as hydrochloride salt) as a potent and selective DPP-4 inhibitor DPP-4 inhibitors with unique pharmacological profile [193]. It is noteworthy that many known DPP-4 inhibitors have The DPP-4 is responsible for the degradation of the incretin the P-1-- P-2 fragment, where the P-1 site contains a proline Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 hormones GLP-1 and GIP and has therefore a strong influ- mimic [10,194]. Pyrrolidine derivatives (vildagliptin and saxa- ence on insulin secretion and glucose homeostasis [184].In gliptin) have been widely explored as DPP-4 inhibitors due contrast to therapy with GLP-1 analogues, because of limita- to DPP-4’s specificity for substrate having an amino- tions due to its swift inactivation, DPP-4 inhibitors increase terminal proline at C-2 [10]. Their cyanopyrrolidine moieties effective incretin levels into a more physiological range [185]. bind to the S1 sub-site and form a covalent bond between So, in the recent years, DPP-4 inhibitors have been noted as the nitrile group and hydroxyl of Ser630 in the catalytic triad. valuable agents for treatment of T2DM. Lack of selectivity Further, their hydroxy adamantyl groups bind to the S2 sub- toward several closely related proline-specific enzymes seems site [195]. Vildagliptin was chemically unstable due to intramo- a possible cause of toxicity [186]. In this review, the discovery lecular cyclisation between the nitrile group and the P-2 basic of some synthetic compounds which may be useful in amine moiety. Saxagliptin has an improved chemical stability approach to new DPP-4 inhibitors as a new anti-diabetic class by introduction of a cyclopropyl ring (cis-4,5-methanobridge) are presented. Structurally, two distinctive classes of DPP-4 to the prolinenitrile which minimises cyclisation [160,196]. The inhibitors have been reported [168]. Peptidomimetic inhibitors DPP-4 inhibitors possessing the electrophilic trap such as a include sitagliptin, vildagliptin and saxagliptin (Figure 2) and nitrile group have low selectivity against other related prolyl

Expert Opin. Drug Discov. (2013) 8(11) 1347 M. Safavi et al.

F F N NH O HO 2 HN N CN N N O NH N 2 F N O C OH CF3 Saxagliptin [244,245] Sitagliptin [243] Vildagliptin [246] DPP-4 IC50: 26 nM DPP-4 IC50: 18 nM DPP-4 IC50: 3.5 nM μ μ DPP8/DPP4 > 400 fold QPP IC50 > 100 M QPP IC50 > 500 M μ DPP9/DPP4 > 75 fold DPP8 IC50: 48 M

CH3 CH O F CH3 3 O N O N F C O + F NH3 NH2 O H3C N Cl- H O N F N CH3 N NH + 3 CF3 N TFA- F F N CH 3 CH CH3 3 1 [189] 2 [189] 3 [190] μ μ μ DPP-4 IC50: 0.025 M DPP-4 IC50: 0.016 M DPP-4 IC50: 0.0058 M μ μ μ QPP IC50 > 100 M DPP-8 IC50: 25 M QPP IC50: 15 M μ μ μ DPP-9 IC50 > 100 M DPP-9 IC50 > 100 M DPP-8 IC50: 46 M μ μ DPP-8 IC50 > 100 M DPP-9 IC50 > 100 M

O O CN H CH3 N CF N N N N 3 H N CN CH3 CH3 N N HCl N HN O N For personal use only. N N H CH3 N S N H S N CH3 N N N N H N O O CH3 H O 4 [191] 5 [193] 6 [194] 7 [197] μ DPP-4 IC50: 0.009 M DPP-4 IC50: 3.8 nM DPP-4 IC50: 0.37 nM DPP-4 IC50: 0.37 nM μ DPP-8 IC50: 17.38 M DPP-8 IC50: 68 nM DPP-8 IC50: 72.4 nM DPP-8 IC50: 260 nM μ DPP-9 IC50: 5.7 M DPP-9 IC50: 60 nM DPP-9 IC50: 105 nM DPP-9 IC50: 540 nM

F F Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 NH2 O N F N N H N N

CF3

8 [163] μ DPP-4 IC50: 0.031 M μ DPP-8 IC50: 78.5 M μ DPP-9 IC50: 41.6 M

Figure 2. Schematic representation of chemical structure of some examples of the peptidomimetic DPP-4.

1348 Expert Opin. Drug Discov. (2013) 8(11) Importance of synthetic drugs for T2DM drug discovery

F F O CN O + - NH3 TFA N N CH3 N N N N N O N N O N F N N NH2 N CH3 CH3 N O NH2 Alogliptin [246] Linagliptin [247] 9 [201] DPP-4 IC50 < 10 nM DPP-4 IC50: 1 nM DPP-4 IC50: 1.2 nM μ μ μ DPP-8 IC50 > 100 M QPP IC50 > 100 M QPP IC50: > 100 M μ μ μ DPP-9 IC50 > 100 M DPP-8 IC50: 40 M DPP-8 IC50 > 100 M μ μ DPP-9 IC50 > 10 M DPP-9 IC50 > 19 M

N N F

N NH2 NH2

N N Cl CH3 O H O2 F S N N N N N O CH N N Cl 3 CH3 H NH2

10 [203] 11 [204] 12 [206] μ μ μ DPP-4 IC50: 0.001 M DPP-4 Ki: 0.006 m DPP-4 IC50: 0.055 M μ μ DPP-4 inhib. in rat: 80% DPP-8 Ki: > 30 M QPP IC50: 63 M μ μ μ Muscarinicreceptor M1 IC50: 1.190 M DPP-9 Ki: > 30 M DPP-8 IC50 > 100 M μ DPP-9 IC50 > 100 M

F H3C CH3 Cl For personal use only. NH2 N O CH3 O NH2 N F H N N F N N HN N O N O C CO2NH2 NH CH3 2 OH 13 [206] 14 [207] 15 [208] μ DPP-4 IC50: 0.018 M DPP-4 IC50: 1.3 nM DPP-4 IC50: 0.48 nM μ μ μ QPP IC50: 22 M QPPIC50: 20 M QPP IC50 > 10 M μ μ μ DPP-8 IC50: 18 M DPP-8 IC50 > 60 M DPP-8 IC50 > 100 M μ μ μ DPP-9 IC50: 27 M DPP-9 IC50 > 60 M DPP-9 IC50 > 100 M Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13

Figure 3. Schematic representation of chemical structure of some examples of the non-peptidomimetic DPP-4 inhibitors.

peptidases, DPP-8 and DPP-9 [197]. The key interactions of and long-lasting inhibitors [200]. Fused bicyclic heteroarylpi- the vildagliptin and saxagliptin structures with DPP-4 active perazine substituted at the g-position of the proline structure site residues are presented in Table 2. in the investigation of L-prolylthiazolidines lacking the elec- Yoshida et al. designed novel pyrrolidine derivatives with- trophilic nitrile was previously explored. Compound (6) out electrophilic nitrile moiety focused on the substituent at (2-trifluoroquinolyl) was the most potent, long-lasting and the g-position of proline moiety of prolylthiazolidine core selective DPP-4 inhibitor. X-ray crystal structure determina- structure towards increasing the affinity to the S2 sub-site of tion of compound (6) indicates that compound (6) made DPP-4 [194,198,199]. According to previous reports, introducing many interactions with the active site of DPP-4 (Table 2). an electron-deficient 4-arylpiperazine results in highly potent The SAR study of fused bicyclic heteroarylpiperazine parts

Expert Opin. Drug Discov. (2013) 8(11) 1349 M. Safavi et al.

Table 2. Key interactions between inhibitor structures and DPP-4 active site residues.

DPP-4 inhibitor Involved inhibitor structure Interaction type DPP-4 residue Study

Linagliptin Amino group on the piperidine Hydrogen bonding interactions Glu205, Glu206 Eckhardt et al. and Tyr662 2007 [202] C-6 carbonyl of the xanthine Hydrogen bonding interactions Tyr631 Quinazoline group Stacking interactions Trp629 Uracil group Stacking interactions Tyr547 Saxagliptin Amino group (primary) Hydrogen bonding interactions Glu205, Glu206 Metzler et al. and Tyr662 2008 [242] Carbonyl group Hydrogen bonding interactions Asn710 Hydroxyl group on the Hydrogen bonding interactions Tyr 547 adamantyl moiety Imidate nitrogen Hydrogen bonding interactions Tyr 547 4,5-Methanopyrrolidine ring van der Waals interactions Val711, Val656, Tyr662, Tyr666, Trp659 and Tyr547 Nitrile of the cyanopyrrolidine Covalent bond Ser630 Sitagliptin b-Amino group Hydrogen bonding interactions Glu205, Glu206 Zhu et al. 2013, and Tyr662 Kim et al. Carbonyl group Hydrogen bonding interactions Tyr547 2005 [163,243] Triazolopiperazine Stacking interactions Phe357 Trifluoromethyl group on Ionic Bonds Arg358 and Ser209 the triazolopiperazine Trifluorobenzyl group Hydrophobic interactions Ser630, His740, Trp659, Tyr631, Tyr662 and Tyr666 Vildagliptin Amino group Salt bridge interactions Glu205, Glu206 Nabeno et al. Carbonyl group Hydrogen bonding interactions Asn710 2013 [195] Hydroxyl group on the Hydrogen bonding interactions His126 and Ser209 adamantyl moiety Imidate nitrogen Hydrogen bonding interactions Tyr547 Nitrile of the cyanopyrrolidine Covalent bond Ser630 6 Amino group of the proline Salt bridge interactions Glu205 and Glu206 Yoshida et al.

For personal use only. Carbonyl group Hydrogen bonding interactions Asn710 2012 [194] Quinolyl ring Stacking interactions Phe357 CH-- p interaction Arg358 Trifluoromethyl on the Imperfect interaction Tyr585 quinolyl ring 7 (teneligliptin) Amino group of the proline Salt bridge interactions Glu205 and Glu206 Yoshida et al. Carbonyl group Hydrogen bonding interactions Asn710 2012 [197] Phenyl on the pyrazolyl ring Hydrogen bonding interactions Ser209 and Arg358 Hydrogen bonding interactions Val207 Piperazinyl ring CH-- p interaction Phe357 Pyrazolyl ring Hydrophobic interactions Phe357 8 Amino group Salt bridge interactions Glu205 and Glu206 Zhu et al. Trifluoromethyl group on -Interactions Tyr585 and Arg356 2013 [163] the triazolopiperazine Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 14 Amino group on the Hydrogen bonding interactions Glu205, Glu206 Maezaki et al. quinoline ring and Tyr662 2011 [207] 2-Isobutyl group Hydrophobic interaction Phe357 2-Oxo group on the Hydrogen bonding interactions Lys554 piperazin-2,5-dione 5-Oxo group on the Hydrogen bonding interactions Tyr631 piperazin-2,5-dione Piperazin-2,5-dione ring Hydrophobic interaction Tyr547 15 Amino group at the piperidine Salt bridge interactions Glu205 and Glu206 Ikuma et al. moiety (primary) 2012 [208] Carbonyl group on the Hydrogen bonding interactions Tyr631 quinoline ring Carboxyl group on the Salt bridge interaction Lys554 benzene ring 3H-imidazo[4,5-c]quinolin- Stacking interactions Tyr547 4(5H)-one moiety

1350 Expert Opin. Drug Discov. (2013) 8(11) Importance of synthetic drugs for T2DM drug discovery

of previous study revealed that the non-linear (L-shaped) DPP-4 inhibitor with excellent selectivity but poor pharmaco- structure was more suitable than the linear (I-shaped) one in kinetic properties [201]. DPP-4 inhibitory activity. Moreover, the X-ray crystal struc- The X-ray crystal structure of linagliptin complexed with ture determination of compound (6) in complex with human DPP-4 indicated the manner in which these residues provided DPP-4 indicated that interaction between the quinolyl ring a good fit (Table 2) [202]. A class of 3,5-dihydro-imidazo and the S2 extensive sub-site plays an important role for [4,5-d]pyridazin-4-ones with different substituent provided. DPP-4 inhibition [194]. Hence, the introduction of another In addition to in vitro DPP-4 inhibitory activity, the effects non-linear structure, a linked bicyclic heteroaryl group on of compounds on the muscarinic receptor M1 and inhibition the piperazine or piperidine moiety, instead of a fused bicyclic of DPP-4 in rats was tested. It should be noticed that signifi- heteroaryl group, was addressed in the latter study which led cant M1 receptor inhibition was a characteristic of some early to discovery of 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyra- xanthines. Compound (10) seems to be a potential candidate zol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine showing very potent DPP-4 inhibitor activity in vitro as well (7), as highly potent, selective, long-lasting and orally active as in vivo and only poor affinity to M1 receptors. The long- DPP-4 inhibitor. The X-ray co-crystal structure of compound lasting strong DPP-4 inhibition (> 70% 24 h post-adminis- (7) in DPP-4 demonstrated that the characteristic five rings of tration) of compound (10) is particularly noteworthy. There- compound (7) fit into the active site of DPP-4 and the key fore, further works on this series, and compound (10)in interaction between the phenyl substituent on the pyrazolyl particular, will be helpful in the development of better drugs ring and the S2 extensive sub-site of DPP-4 not only raised for T2DM [203]. potency, but also increased selectivity (Table 2). Compound Pyrazolopyrimidines are a class of compounds under inves- (7) significantly inhibited the increase of plasma glucose levels tigation. A series of pyrazolopyrimidines with different sub- after an oral glucose load in Zucker fatty rats. Compound (7) stituents on the pyrazole ring which include alkyl, aryl, (teneligliptin) has been approved for the treatment of T2DM substituted aryl and carboxylic ester groups were tested in Japan on June 2012 [197]. in vitro against purified human DPP-4. Favourable The crystal structures of DPP-4 in complex with bound DPP-4 activity, selectivity over DPP-8 and DPP-9 and ample sitagliptin and alogliptin have shown that a sub-pocket opportunity for further optimisation around the pyrazole ring formed by the catalytic residue Ser630 and nearby residues were the three desirable characteristics of this class of com- is usually occupied by a hydrophobic ring group such as the pounds. A 5-aminomethyl imidazolopyrimidines derivative trifluorobenzyl group of sitagliptin or the benzonitrile of alog- compound (11) was the most potent against DPP-4 with no liptin. Two acidic residues -- Glu205 and Glu206 -- in the S2 significant DPP-8/DPP-9 inhibition. The oGTT in ob/ob

For personal use only. sub-site of DPP-4 forms interactions with amine group of mice by compound (11) showed dose-dependent increase in sitagliptin (Table 2). These interactions between sitagliptin plasma insulin levels [204]. and DPP-4 give a large unoccupied space around the right ter- While substituted 4-amino cyclohexylglycine analogues in minal portion (the fused heterocyclic ring) which could be the a-amino acid series showed good activity against modified to generate a new series of DPP-4 inhibitors. With DPP-4 [205], the substituted cyclohexane and piperidine deriv- this rationale, well-established click chemistry was used to atives were prepared and assessed for DPP-4 inhibitory activ- quickly explore the SAR of the linker and the terminal por- ity and selectivity profiles against other proline-specific tion of sitagliptin. A series of 4-(2,4,5-trifluorophenyl) peptidases. In the cyclohexyl with sulphonamide substituent butane-1,3-diamines were designed and elaborated as DPP-4 series, N-methyl-(2,5-dimethylisoxazol-yl)sulphonamide (12) inhibitors. The results showed that compound (8) had desir- showed the most promising potency against DPP-4 and able efficacy, selectivity and pharmacokinetics properties. It excellent selectivity against the off-target enzymes but poor is noteworthy that crystal structures of DPP-4 in complex pharmacokinetic. Among the N-substitution piperidine deriv- Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 with bound compound (8) revealed that the trifluoromethyl atives, 3-(5-aminocarbonylpyridyl piperidine) (13) displayed heterocycle is rotated ~ 180 and directed towards a sub- excellent DPP-4 activity with good selectivity versus other pocket different from the sub-site bound by sitagliptin, pro- proline enzymes [206]. viding clues for the design of new DPP-4 inhibitors. The As mentioned in Table 2, many of the reported DPP-4 key interaction between compound (8) and DPP-4 active inhibitors including vildagliptin and saxagliptin make a cova- site are presented in Table 2 [163]. lent interaction with the Ser630 residue in the S1 pocket. Sita- gliptin and linagliptin form non-covalent interactions with 4.2 Non-peptidomimetic inhibitors the S’1, S’2 or S2 extensive sub-sites in addition to the Monocyclic, bicyclic, bicyclic lactams and triazolopyridazines- S1 and S2 sub-sites. It appears that excess interactions may substituted 3-aminopiperidines were synthesized and evalu- increase DPP-4 inhibition beyond the level yielded by the ated for in vitro inhibition of human DPP-4, QPP, DPP-8 fundamental interactions with the S1 and S2 sub-sites and and DPP-9. Bicyclic lactams series were potent (DPP-4 are more effective than forming a covalent bond with -- IC50: 1.2 8 nM) and in general had good-to-excellent selec- Ser630 in the S1 subunit [195,207]. Design of novel non- tivity. Compound (9) was found to be the most potent covalent inhibitors of DPP-4 using structural information

Expert Opin. Drug Discov. (2013) 8(11) 1351 M. Safavi et al.

derived from DPP-4 structures co-crystallised with small mol- competitive inhibitor with two moieties to bind with SGLT: ecules originating from different chemical classes is now a vital a glucose moiety connected with an oxygen atom (O-glucoside) investigation in medicinal chemistry. and a hydrophobic aglycone moiety [209,211]. The first- Based on the X-ray co-crystal structure of some com- generation SGLT2 inhibitors with O-glycosidic bond were pounds, the hydrogen bonding interaction with Lys554 may discontinued due to their short half-lives in vivo resulting be applicable in the novel design of DPP-4 inhibitors. Hence, from glycosidase cleavage [211,212]. Second-generation SGLT2 Maezaki et al. developed a novel series of non-covalent quin- inhibitors adopted other forms of glycoside linkage resistant oline-based inhibitors to target the side chain of Lys554. Syn- to glycosidase activity such as C-glucoside structure [213]. thesis and evaluation of designed compounds against DPP-4, QPP, DPP-8 and DPP-9 enzyme and determination of 5.1 C-glycoside analogues of SGLT2 inhibitors absorption, distribution, metabolism and excretion and phar- Many C-aryl glycoside analogues containing conjugated aryl macokinetic profiles revealed 1-[3-(aminomethyl)-4-(4-methyl- moiety with glucose moiety by C-- C bond instead of instable phenyl)-2-(2-methylpropyl) quinolin-6-yl]piperazine-2,5-dione C-- O-- C bond have been designed and synthesized [179,214]. compound (14) -- a potent, selective and orally active Among these analogues, dapagliflozin has been used as a DPP-4 inhibitor with long-lasting ex vivo activity in dogs and lead compound as many synthetic derivatives have been fur- potent glucose-lowering effects in rats. A docking study of com- ther made on its SAR data. A series of fluorinated analogues pound (14) suggested that an efficient fit into the binding site of dapagliflozins were designed and synthesized by incorpo- and a hydrogen-bonding interaction with the side chain of ration of a gem-difluoromethylene group at C-4 position. Lys554 are important in enhancing the inhibitory activity. The in vitro inhibitory activities of these series against human Also, in comparison with other members of this series, it seems SGLT2 showed that some of the analogues (compound 16) that compound (14) achieved excellent activity by taking advan- with CF2 at C-4 are better SGLT2 inhibitors compared tage of the desirable piperazin-2,5-dione substituent and form- with dapagliflozin (Figure 4) [215]. ing hydrophobic and two hydrogen-bonding interactions, The structural similarity of D-xylose and D-glucose and the including the one with Lys554 (Table 2) [207]. positive results of O-xylosides and N-b-D-xylosides [216] led to Ikuma et al. found a potent DPP-4 inhibitor by high- the design of a new series of C-linked indolylxylosides. SARs throughput screening of laboratory chemical library and studies indicated that a p-cyclopropylphenyl group in the dis- proper optimisation based on results of published DPP-4 tal position and substituents at the 7-position of the indole enzyme-inhibitor docking study. Further docking studies moiety were necessary for optimum inhibitory activity. The were carried out to design a strategy for optimisation of lead pharmacokinetic and animal studies demonstrated that the

For personal use only. compound with 3H-imidazo[4,5-c]quinolin-4(5H)-one as most potent compound 7-substituted indolylxlyosides bearing skeleton. Compound (15) with 2-chloro-5-fluorobenzylsub- a distal p-cyclopropylphenyl group (17) is metabolically stable stituent on the imidazoquinoline group was found as potent with significant efficacy on lowering blood glucose levels of and highly selective DPP-4 inhibitor [208]. The results of streptozotocin-induced diabetic rats [217]. docking study are shown in Table 2. Ikegai et al. investigation led to the discovery of other C-glucoside SGLT2 inhibitors with azulene motifs [218]. 5. New synthetic compounds as Although azulene is not a common motif in medicinal chem- SGLT2 inhibitors istry of anti-diabetic drug discovery, a search of the literature indicates that certain azulene derivatives possess significant Inhibition of glucose reabsorption and increasing urinary pharmacological and therapeutic activity [219-221]. Hence, a glucose excretion lead to a negative energy balance, making series of C-glucosides with azulene rings in the aglycone moi- these series of compounds a unique promising therapeutic ety was synthesized; SAR of azulene-derived C-glucoside and Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 class with potential to reduce body weight in T2DM [172]. the inhibitory activities towards hSGLT1 and hSGLT2 were Only sugars in a hexose and the D-configuration are translo- explored. Incorporation of a phenolic hydroxyl group at the cated by SGLT. The hydrogen bonding between SGLT2 and central benzene ring afforded a more potent and selective hydroxy groups at C-2, C-3 and C-4 and hydrophobic inter- SGLT2 inhibitor (18), which exerted a strong and sustained actions with the C-6 methylene group of the pyranose are the anti-hyperglycaemic effect in rodent diabetic models. key interactions in determining sugar specificity [209,210]. The A mono choline salt of compound (18) (YM543) was selected b-glucosides with large ring structures such as aromatic aglu- as a clinical candidate for use in treating T2DM [218]. cones and the aglucones themselves are well accommodated A new class of potent and selective SGLT2 inhibitors, by at the sugar-binding site and not translocated. They act as modifying the glycone side chain incorporating a structurally inhibitors of the transport [174,209]. Various O-, C-, N-and novel dioxabicyclo-[3.2.1]octane ring system, was pre- S-glucosides have been synthesized with high affinity and pared [222]. At first, a series of C-5-spirocyclic C-glycoside high specificity for SGLT2 that are in the different stages of were synthesized with relatively good potency and selectivity clinical development [209]. The b-glucoside phlorizin, the first for human SGLT2 but suboptimal pharmacokinetics [223]. SGLT2 inhibitors, is a O-aryl glycoside and non-selective The medicinal chemistry strategy by innovative chemistry

1352 Expert Opin. Drug Discov. (2013) 8(11) Importance of synthetic drugs for T2DM drug discovery

OH CH3 O HO OH CH3 Cl O

O HO O O O O HO HO HO OH HO OH HO OH OH OH OH Phlorizin [215] Dapagliflozin [214] Sergliflozin-A [249] SGLT2 IC50: 46.03 nM SGLT2 EC50: 1.1 nM SGLT2 Ki: 2.39 nM SGLT1/SGLT2: 1200 fold SGLT1/SGLT2: 296 fold

CH3 Cl O HO F O O HO HO N O HO OH F OH F OH OH HO OH OH 16 [215] 17 [217] 18 [218] SGLT2 IC50: 0.35 nM SGLT2 EC50: 47 nM SGLT2 IC50: 8.9 nM SGLT1/SGLT2: 6 fold SGLT1/SGLT2: 280 fold

CH3 NH O CH3 Cl O HO N N O O (CH3)3 O HO HO

HO OH HO OH OH OH

For personal use only. 19 [222] 20 [225] 21 (pseudo-sergliflozin) [227] μ SGLT2 IC50: 0.887 nM SGLT2 EC50: 3.85 M SGLT2 IC50: 2.45 nM SGLT1/SGLT2 > 2234 fold SGLT1/SGLT2 > 200000 fold

O S S Cl HO N N HO OH OH O N

HO OH OH 22 [228] 23 [216] Inhibition rate of blood glucose SGLT2 EC50: 161 nM

Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 levels in oGTT: 74.85% SGLT1/SGLT2: 1.3 fold

Figure 4. Schematic representation of chemical structures of some SGLT2 inhibitors together with their experimental inhibitory and selectivity activities.

that allowed difficult, yet very desirable, targets to be synthe- C-5 (in place of the spirocycle) brought more anticipation sized in an analogue-friendly fashion and the development of to reduce the rate of human Phase II metabolism and further a pharmacokinetics/pharmacodynamics (PKPD) model improvement of the potency. These efforts supported the brought more hope. These efforts led to deprioritisation of advancement of compound (19) (PF-04971729) into clinical the C-5-spirocyclic C-glycoside SGLT2 inhibitors and focus- development that is being evaluated for the treatment of ing on the dioxabicyclo[3.2.1]octane class. It is believed that T2DM [222]. the bridged ketal system would confer rigidity with poten- Vyas et al. performed a ligand-based 3D quantitative SARs tially positive impact on potency and selectivity. Moreover, (QSARs) study on C-aryl glucoside SGLT2 inhibitors introduction of a hydroxymethylene H-bond donor group at (180 analogues), which belong to various diversified

Expert Opin. Drug Discov. (2013) 8(11) 1353 M. Safavi et al.

structures such as benzisothiazole, indolizine-b-D-glucopyra- Among them, the 4-chloroindolyl-N-xyloside with the noside, thiazolylmethylphenyl, pyridazine, thiazole and 4-cyclopropylbenzyl at the distal position (23) was found the pyrimidinylmethylphenyl glucoside analogues. Comparative most potent inhibitor with no selectivity for SGLT2 over molecular field analysis (CoMFA) and comparative molecular SGLT1. According to pharmacokinetic data, compound similarity indices analysis (CoMSIA) were used to further (23) was metabolically stable with a low clearance and good explore the structural requirements of C-aryl glucoside ana- oral bioavailability in Sprague Dawley rats [216]. logues for SGLT2 inhibition. CoMFA and CoMSIA contour map analysis offered enough information to understand the 7. Conclusion importance of the substituent at particular positions with respect to steric, electrostatic, hydrophobic, hydrogen-bond More recently, the need to develop new drugs for T2DM as a donor and acceptor properties for better activity of C-aryl gluco- multi-causal and complicated disease has been emphasized, as side SGLT2 inhibitors. For example analysis of CoMFA and the worldwide incidence of this disease is increasing dramati- CoMSIA contour plots revealed the importance of hydrophobic cally. Various drug options are now available for the manage- and hydrogen-bond donor and acceptor properties [224]. ment of T2DM, but almost all are associated with restrictions and most do not address all aspects of the defects in diabetic 5.2 SGLT2 inhibitors with other structures patients. The recently introduced DPP-4 and SGLT2 inhibi- The application of ligand-based virtual screening strategy tors effectively lower the blood glucose without weight gain comprising the combination of pharmacophore model with and risk of hypoglycaemia. shape-based scoring and structure clustering analysis led to The co-crystal structures of human DPP-4 with some the discovery of non-glycoside SGLT2 inhibitors. A total of approved inhibitors are available. So, in recent years, new syn- 7989 compounds matching all the features described by phar- thetic DPP-4 inhibitors with diverse chemical structures have macophore model were then subjected to shape-based scoring been found, according to the X-ray crystal structure of and structure clustering analysis. Totally, 80 compounds with DPP-4 and computer-modelling studies. Remarkable creativ- high score and structurally diverse scaffolds were selected for ity and thoughts have been demonstrated by medicinal chem- biological testing, and out of these, three compounds showed ists in designing novel and potent series of DPP-4 inhibitors. µ inhibition of SGLT2 with EC50 <10 M. The non-glycoside Various SGLT2 inhibitors based on the glucoside structure of µ compound (20) with EC50 = 3.85 M was the most potent phlorizin, sergliflozin, dapagliflozin, canagliflozin and other compound [225]. inhibitors in clinical trial have since been proposed. Alternative Most SGLT2 inhibitors in clinical trials are taken from two candidate SGLT2 inhibitors that have also been considered

For personal use only. distinct series: C-aryl glycosides (e.g., dapagliflozin) and include modified sugar rings, N-glucosides, S-glucosides, non- O-aryl glycosides (e.g., sergliflozin and remogliflozin) [223]. glycoside and, more recently, bridged ketal ring, azulene The abovementioned compounds were C-glucoside deriva- motifs. The other promising agents targeting novel molecular tives but showed higher cancer risk [226]. It is thought that mechanisms are under development. The hope is to discover the metabolic instability of the O-glucoside SGLT2 inhibitors more selective and effective anti-diabetic agents in the can be solved by modifying the sugar core of sergliflozin-A. near future. Several small-molecule carbohydrate mimics such as pseudo- sergliflozin were synthesized by a region- and stereo-selective 8. Expert opinion allylic substitution reaction. Then the SGLT2/SGLT1 inhibitory activities of these newly synthesized compounds were Despite a rapid increase in the number of drugs available to studied. The endocyclic oxygen atom of sergliflozin-A was treat hyperglycaemia, diabetes still remains a major global replaced by a methylene unit to render the molecule free concern. Although three oldest classes comprising insulin, sul- Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 from glycosidase degradation. In this way, compound (21) phonylureas and the biguanides are effective in improving was found as a potent and selective inhibitor of SGLT2 that outcome, they are unable to sustain adequate glycaemic considered a lead compound for further development [227]. control over time in the diabetic patients. A variety of anti- A series of thiadiazole-based S-glycosides were synthesized hyperglycaemic drugs with different and complementary from D-glucose, D-galactose and a variety of phenylacetic acids mechanisms of action are currently available. Moreover, the and then evaluated in vivo with an oGTT test. Of these, use of current medications is often limited by their side 5-benzyl-1,3,4-thiadiazol-2-yl 1-thio-b-D-glucopyranoside effects, mostly sudden hypoglycaemia, weight gain, gastroin- (22) was the most efficacious to suppress the blood glucose testinal effects or oedema. These factors necessitate the ongo- excursion during oGTT with the inhibition rates of blood ing quest for novel agents that would address fundamental glucose levels equal to 74.85% [228]. defects of T2DM and have minimal adverse effects. Since, N-linked glycosides were expected to have greater Among the main anti-diabetic drug classes, DPP-4 and metabolic stability compared to O-glucosides, a novel series SGLT2 inhibitors are novel and promising therapy for of N-linked b-D-xylosides were synthesized and evaluated T2DM. The details of synthesis backgrounds of many new for inhibitory activity against SGLT2 in a cell-based assay. DPP-4 inhibitors, in the recent years, are described in this

1354 Expert Opin. Drug Discov. (2013) 8(11) Importance of synthetic drugs for T2DM drug discovery

review. In this review, the structures of some compounds with The X-ray crystal structure of SGLT2 is yet not available; biological properties are also presented. Phenylalanine and thus, to explore the structural requirements for SGLT2 inhi- cyclohexylalanine derivatives and imidazopiperidine-based bition, the ligand-directed drug model was used to screen b-amino acid derivatives were designed based on the observa- active compounds as templates. Ligand-based screening tech- tion that modification of the phenylalanine, cyclohexylalanine niques mainly focus on comparing molecular similarity anal- or piperazine moiety improved the DPP-4 potency by several yses of compounds with known and unknown moiety. The folds. Also the 3-fluoropyrrolidine analogues obtained by 3D QSAR methods of CoMFA and CoMSIA models have replacing the pyrrolidine ring compounds (1)and(2) showed been developed as ligand-based approaches. As mentioned, more activity compared to parent compound [189,190]. Since CoMFA and CoMSIA models were successfully used in pro- bicyclo[3.3.0]octane derivative with pyrrolidine-2-carbonitrile viding useful information for designing new SGLT2 inhibi- was previously reported to be a potent DPP-4 inhibitor [191], tors [224]. Computer-aided drug design plays an important azobicyclo[3.3.0]octane compounds were synthesized. The dis- role in drug discovery and development and provides useful covery of anagliptin was according to studies showed that pyr- insights into experimental findings and mechanism of action azolo[1,5-a]pyrimidine functions as a bioisostere conveying and new suggestions for molecular structures to synthesize. much metabolic stability and safety [193]. In this way, large databases of compounds can be tested A costly component of drug discovery approaches is in silico with cheaper and faster techniques before submitting structure-based screening (docking), which is a design strategy to in vitro expensive synthesis [229]. for new chemical entities, or optimisation of lead compounds Most classic anti-diabetic drugs target the major pathophys- identified by other methods, using the 3D structure of the iological defects in T2DM, namely insulin resistance and DPP-4. The 3D structure of DPP-4 could be obtained by impaired insulin secretion, while the new developing drugs X-ray or nuclear magnetic resonance studies or from homol- focus on other options such as SGLT2 inhibitors that affect ogy models. The protein data bank is a repository for the the kidney through insulin-independent mechanisms. 3D structural data of proteins. The crystal structures of Recently, PPARa/dualagonists[230], SIRT1 activators [231,232], DPP-4 have been previously disclosed and the discovery of glycogen phosphorylase inhibitors [233] and protein tyrosine teneligliptin performed by aid of mentioned in silico methods phosphatase 1B inhibitors [233-235] were luckily designed for which comprise computationally assessed ligand-binding the treatment of T2DM. interactions with DPP-4. Non-peptidomimetic inhibitors of There is no doubt that T2DM and its related complica- DPP-4 such as 3-aminopiperidines with bicyclic lactams sub- tions are associated with oxidative stress that plays a role in stituents were originated from sitagliptin -- a peptidomimetic the pathogenesis of T2DM. Antioxidant (natural or synthetic)

For personal use only. DPP-4 inhibitor, X-ray crystallographic structure along with therapy can protect b-cells from apoptosis and might posi- molecular modelling [201]. Also non-covalent quinoline-based tively work in control of hyperglycaemia by activating the inhibitors which target the side chain of Lys554 were designed production and release of insulin [13,66,74]. based on the X-ray co-crystal structure of some compounds Finding new targets and new faster and cheaper synthesis containing hydrogen bonding interaction with Lys554 [207]. methods are the main goal in T2DM drug discovery. No sin- Numerous DPP-4 inhibitors that were discovered and/or opti- gle diabetes treatment is best for everyone as each person mised using in silico methods have reached the level of clinical responds in a different way to medication. Together, the avail- studies or have gained approval of use in some countries. able and rising drug candidates should provide physicians Stability and selectivity of SGLT2 inhibitors is an with a broad range of pharmacological choices to successfully important issue in drug design. The SARs studies of individualise patient treatment. phlorizin and other candidates led to discovery of another selective and potent SGLT2 inhibitor with excellent phar- Declaration of interest Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13 macokinetic properties. Discovery of dioxabicyclo[3.2.1] octane was supported by analogue-friendly fashion and The authors state no conflict of interest and have received no PKPD model [222]. payment in preparation of this manuscript.

Expert Opin. Drug Discov. (2013) 8(11) 1355 M. Safavi et al.

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