Pharmacological Reports Copyright © 2012 2012, 64, 10551065 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences
Review
11b-Hydroxysteroid dehydrogenase type 1: potential therapeutic target for metabolic syndrome
Amit Joharapurkar1, Nirav Dhanesha1, Gaurang Shah2, Rajendra Kharul3, Mukul Jain1
1 Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India
2 K. B. Institute of Pharmaceutical Education and Research, Gandhinagar 382023, India
3 Advinus Therapeutics Ltd. Quantum Towers, Plot No. 9, Rajiv Gandhi Infotech Park, Phase – I , Hinjewadi, Pune – 411057, India
Correspondence: Amit Joharapurkar, e-mail: [email protected]
Abstract: Obesity and associated metabolic syndrome is one of the greatest health threat to the modern society. Cortisol excess and the gluco- corticoid receptor signaling pathway in the metabolically active tissues have been implicated in the development of diabetes and obesity. The key enzyme in the regeneration of intracellular cortisol is 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1). 11b-HSD1 increases local cortisol production in metabolically active tissue types such as adipose and liver. Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. Clini- cal and preclinical studies indicate that 11b-HSD1 inhibitors are likely to exert major pharmacological actions in metabolically ac- tive tissues. These effects suggest that inhibition of 11b-HSD1 in vivo may be a novel therapeutic target for obesity, diabetes, and metabolic syndrome.The advancement of numerous structural classes of selective 11b-HSD1 inhibitors further indicates that more refined design and screening for isoform and tissue selectivity would yield potential therapeutics in this area.
Key words: 11b-hydroxysteroid dehydrogenase type 1, metabolic syndrome, obesity, diabetes, glucocorticoids, liver, adipose
Abbreviations: 11b-HSD – 11b-hydroxysteroid dehydroge- which is intra-abdominal fat accumulation, signifi- nase, ACTH – adrenocorticotropic hormone, DIO – diet induced cantly increases the risk of mortality as well as obesity, G6Pase – glucose 6-phosphatase, GR – glucocorticoid comorbidities such as dyslipidemia, hypertension, receptor, HGO – hepatic glucose output, MR – mineralocorti- coid receptor, PEPCK – phosphoenol pyruvate carboxykinase type 2 diabetes mellitus, arthritic conditions and can- cer. Obesity is closely associated with insulin resis- tance, which eventually results in hyperinsulinemia. A chronic hyperinsulinemic state causes excessive in- Introduction sulin action in kidney, arterial walls, and sympathetic nervous system, resulting in elevated risk of increased blood pressure [27]. The metabolic syndrome (or syn- Obesity is one of the most important contributors to ill drome X) is a collection of these associated disorders. health in the current century [26]. Central obesity, Prevalence of metabolic syndrome is largely in-
Pharmacological Reports, 2012, 64, 10551065 1055 creased by sedentary lifestyle, though genetic disposi- [16]. Cushing’s syndrome, primarily caused by excess tion and environmental factors do play a role in the cortisol production, has a cluster of symptoms which etiology [19]. The United Kingdom Prospective Dia- include impaired glucose tolerance due to insulin re- betes Study (UKPDS) is one of the largest clinical re- sistance and increased gluconeogenesis. Many Cush- search studies of diabetes [53]. It indicates that the ing’s syndrome patients show overt diabetes. Con- life threatening complications of type 2 diabetes can versely, a deficit of cortisol production (Addison’s be significantly reduced by appropriate treatment. For disease) results in decreased HGO and occasionally example, 1% reduction in glycosylated hemoglobin hypoglycemia [2]. Such changes in cortisol levels (HbA1c) level correlated with a 7% reduction in over- modulate global glucose metabolism even when the all mortality and an 18% reduction in combined fatal secretion and action of other hormones involved in and non-fatal myocardial infarction. However, only 4 glucose homeostasis is unimpaired. Furthermore, out of 10 patients treated for diabetes meet the treat- monogenic rodent models for the metabolic syn- ment targets, forcing clinicians to move from initial drome, e.g., the leptin-deficient ob/ob mouse or the treatment with one agent to more aggressive interven- leptin-resistant Zucker rat, display overall increased tions with multiple oral therapies, as well as insulin secretion of glucocorticoids [11]. Glucocorticoids im- [39]. Hence, oral therapeutic agents that produce bet- pair insulin-dependent glucose uptake in the periph- ter glycemic control as well as treat related disorders eral tissues, enhance glucose production in the liver of metabolic syndrome are constantly needed in cur- and inhibit insulin secretion from pancreatic b cells rent medicine. [51]. Thus, cortisol excess can be correlated with dia- betes mellitus in clinical settings. Consequently, GR antagonism has been tested as a strategy for regulat- ing HGO in vitro, in animal disease models, and in Glucocorticoids and hyperglycemia humans [20]. However, long-term systemic GR an- tagonism may not be a viable approach for the treat- ment of type 2 diabetes, because it may lead to symp- Glucocorticoids are named in recognition of their pri- toms of adrenal insufficiency (nausea, vomiting, and mary role in glucose metabolism, although they have exhaustion) and activation of the hypothalamic- anti-inflammatory properties and produce multiple pituitary-adrenal (HPA) axis, causing stimulation of effects on protein, carbohydrate, lipid, and nucleic the adrenal cortex (adrenal hyperplasia) and increased acid metabolism [5]. Glucocorticoids raise blood glu- cortisol secretion [29]. cose levels by functionally antagonizing the action of insulin. Typically, they inhibit glucose disposal and promote hepatic glucose production. The change in hepatic glucose output (HGO) is primarily driven by an increase in gluconeogenesis, a result of increased mobilization of gluconeogenic precursors, direct tran- 11b-HSD 1 and obesity-related disorders scriptional stimulation of gluconeogenic enzymes (e.g., phosphoenol pyruvate carboxykinase – PEPCK and glucose 6-phosphatase – G6Pase), and interfer- The design of the therapeutic approaches targeting ence with insulin signal transduction in the liver [5, glucocorticoid was based on the observations that ma- 51]. Glucocorticoids also regulate adipose tissue dif- jor determinant of corticosteroid action was the level ferentiation, function and distribution, and in excess, of free cortisol in the plasma and the densities of GR cause reversible visceral obesity with multiple meta- and mineralocorticoid receptor (MR) in target tissues bolic disorders, as typically observed in Cushing’s [51]. However, current research has highlighted the syndrome [3]. Activation of glucocorticoid receptor tissue-specific metabolism of glucocorticoids, notably (GR)a, in fat cells stimulates lipoprotein lipase (LPL) by 11b-hydroxysteroid dehydrogenase (11b-HSD), mRNA synthesis and an increase in its activity, which which alters tissue glucocorticoid levels and hence its favors lipid mobilization and triglyceride accumula- action on the receptors [52]. 11b-HSD catalyzes the tion [47]. Thus enhanced GRa expression in visceral interconversion of inert 11-ketosteroids, cortisone and adipocytes may account, at least in part, for the vis- 11-dehydrocorticosterone (11-DHC), to their active ceral fat obesity in patients with Cushing’s syndrome 11-hydroxy forms, cortisol and corticosterone.
1056 Pharmacological Reports, 2012, 64, 10551065 11ß-hydroxysteroid dehydrogenase 1 in metabolic syndrome Amit Joharapurkar et al.
C
Fig. 1. Activity of 11b-HSD in human and rodents
The action of glucocorticoids on target tissue is regu- responsiveness to glucocorticoids in skeletal muscle lated by two isoforms of the enzyme 11b-HSD, namely and adipose tissue has been implicated in the meta- 11b-HSD1 and 11b-HSD2 in tissue-specific manner bolic syndrome [57]. Clinically, insulin resistance and [52]. 11b-HSD1-dependent reaction generates active hypertension are associated with increased GRa glucocorticoids which bind to the GR in insulin sensi- mRNA and its receptor numbers in skeletal muscle, tive glucocorticoid target tissues like liver, lung and adi- and a positive association between mRNA levels both pose, while the 11b-HSD2-dependent reaction impedes for GR and 11b-HSD1 in skeletal muscle is observed binding of glucocorticoids to the mineralocorticoid re- for insulin resistant status [47]. These results suggest ceptor in kidneys and colon. This enzymatic reaction is that GR and 11b-HSD1-mediated regulation of intra- shown diagrammatically in Figure 1 and important cellular glucocorticoid action in skeletal muscle may functional differences are summarized in Table 1. play a role in the pathogenesis of the metabolic syn- 11b-HSD1 expression is considered as a major drome. Hence, it is hypothesized that 11b-HSD1 inhi- etiological factor of obesity [57]. Although circulat- bition in obese people who develop impaired glucose ing glucocorticoid concentrations are not elevated in tolerance may protect them from progression to type 2 prevalent forms of human obesity, locally enhanced diabetes. Elevated 11b-HSD1 levels in adipose tissue
Tab. 1. Characteristics of two isoforms of 11b-HSD [11]
Characteristics 11b-HSD1 11b-HSD2 Chromosomal location 1q32.2 16q22 Size Gene: 30 kb, 6 axons Gene: 6.2 kb, 5 axons Protein: 292 aa, 34 kDA Protein: 405 aa, 44 kDA Enzyme family SDR superfamily, encoding gene SDR26C1 SDR superfamily, encoding gene SDR9C3 Tissue expression Liver, adipose, brain, lung, gonads, Kidney, colon, salivary glands, placenta pituitary Enzyme kinetics In vitro bi-directional Only dehydrogenase In vivo mainly reductase, High affinity (Km- nM) Low affinity (Km- µM) Cofactor NAD Cofactor NADP (H) Function Supplies cortisol to GR Protects MR from cortisol
Pharmacological Reports, 2012, 64, 10551065 1057 Tab. 2. Summary of preclinical and clinical developments of 11b-HSD1 inhibitors
Compound Route of administration Development status Originator Licensee INCB13739 Oral Phase IIb Incyte Corporation AZD4017 Oral Phase I AstraZeneca AZD8329 Oral Phase I AstraZeneca JTT-654 Oral Phase I Japan Tobacco AKROS Pharma AMG-221 Oral Phase I Biovitrum Amgen RG 4929 Oral Phase I Roche RG7234 Oral Phase I Roche BMS 816336 Oral Phase I Bristol-Myers Squibb Undisclosed Undisclosed Preclinical Vitae Pharmaceuticals Boehringer Ingelheim BVT 3498 Undisclosed Discontinued Phase II Biovitrum INCB- 20817 Oral Discontinued Phase I Incyte Corporation PF- 915275 Oral Discontinued Phase I Pfizer
in human obesity and the phenotype of two murine lower plasma cholesterol level and a higher HDL to models overexpressing 11b-HSD1 in adipose tissue total cholesterol ratio. On the other hand, upregulation and liver provided evidence that inhibition of gluco- of 11b-HSD1 expression selectively in adipose tissue corticoid regeneration, especially in fat, might be leads to a model of metabolic syndrome in mice [33]. a therapeutic target for metabolic syndrome. 11b- Similar symptoms of metabolic syndrome are evident HSD1–/– mice are viable and healthy, except that they in mice having specific overexpression of 11b-HSD1 have adrenal hyperplasia and hyper-responsiveness to in liver [38]. Clinically, adipose tissue 11b-HSD1 exogenous ACTH in vitro and in vivo to compensate expression and/or activity in human obesity and for their decreased production of active glucocorti- upregulation of glucocorticoid receptors are equally coids [22]. These mice are protected from hyperglyce- well defined [57]. Regeneration of glucocorticoids by mia, display lower plasma triglyceride levels driven 11b-HSD1 in visceral fat contributes substantially to by increased hepatic expression of enzymes involved the concentration of cortisol in the portal vein and in fat catabolism (e.g., carnitine palmitoyltransferase-1 therefore is an important determinant of the develop- (CPT-1), acyl-CoA oxidase (ACO) and uncoupling ment of insulin resistance associated with abdominal protein-2 (UCP-2), etc.) and their coordinating tran- obesity [43]. Interestingly, feeding of HF diet to hepa- scriptional factor, PPARa, have increased HDL- tocyte RXRa KO mice resulted in dyslipidemia and cholesterol with a marked increase in plasma and liver hyperleptinemia as well as impaired angiogenic re- mRNA level for apolipoprotein AI, thus showing an sponse, and cell apoptosis. These results argue for in- improved cardioprotective serum lipid profile and en- dependent participation of dyslipidemia and hyper- hanced hepatic insulin sensitivity [36]. Similarly, dis- leptinemia in pathology of angiogenic response asso- ruption of 11b-HSD1 in an obesity/diabetes prone ciated with metabolic syndrome [40]. strain results in a more favorable adipose tissue distri- 11b-HSD1 is expressed in islets of Langerhans iso- bution as well as protection from diabetes and weight lated from ob/ob mice and also from human pancreas gain upon high-fat feeding, with less fat pad weight [13]. Higher levels of 11b-HSD1 mRNA and enzyme despite no change in feed intake [37]. Moreover, activity have been correlated with the appearance of 11b-HSD1–/– mice are insulin-sensitized, notably in diabetes and are increased further with disease progres- adipocytes in vitro and adipose tissue ex vivo (de- sion. In Zucker fatty rats, troglitazone-induced im- creased resistin and TNF-a, but increased adiponectin provement in metabolic abnormalities correlated with and PPARg). Interestingly, on a high-cholesterol diet, a 40% decline in 11b-HSD1 mRNA in the islets [15]. wild-type mice showed a switch in lipoprotein profile Glucocorticoids impair insulin signaling at multi- from HDL to LDL, whereas 11b-HSD1–/– mice have ple levels. It decreases total IRS1 protein expression
1058 Pharmacological Reports, 2012, 64, 10551065 11ß-hydroxysteroid dehydrogenase 1 in metabolic syndrome Amit Joharapurkar et al.
and also increases Ser307 phosphorylation, which Mechanism of 11b-HSD enzyme inhibition consequently decreases the affinity of IRS1 for the in- sulin receptor and increases IRS1 degradation [1]. The resolved crystal structure indicates that 11b- Glucocorticoid excess induces lipolysis generating HSD1 exists as a homodimer [24, 61], which func- free fatty acids in circulation and their increased up- tions as a reductase enzyme. Many species variant of take in peripheral tissues [14], which activates PKC, 11b-HSD1 have been cloned, which indicates a clear an important mediator of insulin resistance. Selective understanding of sequence information. Comparison 11b-HSD1 inhibition decreases pSer307 IRS1, in- of the primary structures reveals six highly variable creases pThr308 Akt/PKB, and decreases lipogenic segments, which possibly constitute the basis for the and lipolytic gene expression that may represent an differences observed in kinetic and inhibitor charac- important mechanism underpinning their insulin- teristics [25]. sensitizing action [35]. Overall, most compounds are active site inhibitors [55]. Inhibitory mechanism of the arylsulfonamido- thiazole compounds (BVT compounds) by kinetic analysis revealed that the BVT compounds display a complex pattern towards different 11b-HSD species 11b-HSD1 inhibitors and treatment of forms, in contrast to carbenoxolone, which shows obesity related disorders tight binding behavior [25]. It has been observed that both carbenoxolone and BVT-528 bind within the substrate binding pocket. However, carbenoxolone binds tightly, at least to the human and mouse en- It has been hypothesized that decreasing glucocorti- zyme, whereas BVT-528 binds only to the human coid activity in adipose tissue and liver might protect form. These observations revealed the major determi- against the detrimental metabolic consequences of nants of the active site binding. A set of amino acid obesity. Derivatives of the licorice root (Glycyrrhiza residues in the active site, including Ala172 and the glabra), including glycyrrhetinic acid and its syn- catalytic triad Ser170, Tyr183, and Lys187, makes im- thetic hemisuccinyl ester, carbenoxolone, are potent portant interactions with inhibitors and is therefore (IC50 nM in vitro) but non-specific 11b-HSD inhibi- the key determinant of binding affinity for these small tors [34]. A variety of endogenous steroids and their molecule inhibitors. It has been derived that sulfona- metabolites, as well as bile acids such as chenodeoxy- mide based inhibitor functions as a simple substrate cholic acid, have 11b-HSD inhibitory properties [30]. competitive inhibitor, since it occupies the substrate- Studies with 11b-HSD inhibitors using the proto- binding site and neither perturbs the catalytic site nor typic drug, carbenoxolone, showed hepatic insulin affects the NADP(H) binding [55]. In contrast, tria- sensitization in lean healthy subjects [58] and patients zole based inhibitors inhibit 11b-HSD1 in a mixed in- with type 2 diabetes but not obese men [43]. The insu- hibitor mode, since it occupies the substrate binding lin sensitization appears due to reduced hepatic glu- site and alters the catalytic site residues and cose production and glycogenolysis, rather than any NADP(H) binding as well. effect on peripheral glucose uptake, perhaps because carbenoxolone fails to inhibit 11b-HSD1 in adipose tissue in rats or humans [32]. This suggests that a suc- cessful inhibitor for the treatment of obese patients Different classes of 11b-HSD1 inhibitors with type 2 diabetes or metabolic syndrome should be effective in adipose tissue. Nonselective licorice- Natural inhibitors based compounds also potently inhibit 11b-HSD2 causing renal sodium retention, hypertension and hy- Naturally occurring 11b-HSD1 inhibitors include pokalemia [45]. They also have effects on other non-selective glycyrrhetinic acid (Ki = 1.87 µM), its short-chain dehydrogenases, such as 15-prostaglandin derivatives from licorice root (Glycyrrhiza glabra) dehydrogenase and on gap junctions [42], though [34], and selective flavones (IC50 = 18 µM) or 2’- these effects occur at higher concentrations than hydroxyflavones (IC50 = 10 µM) from fruits and vege- 11b-HSD inhibition. tables [46], although non-selective, carbenoxolone
Pharmacological Reports, 2012, 64, 10551065 1059 (Ki = 17 nM), a synthetic hemisuccinate derivative of Triazole based inhibitors from Merck glycyrrhetinic acid, is one of the potent 11b-HSD1 in- hibitors [58]. In addition to its effects on type 2 diabe- Merck identified triazole compound 544 as a potent tes, carbenoxolone improved cognitive function in and selective inhibitor with human 11b-HSD1 IC50 of healthy elderly men and type 2 diabetics [44] suggest- 7.8 nM through high-throughput screening [23]. ing that 11b-HSD1 inhibitors may have expanded Oral administration of compound 544 at 10 mg/kg therapeutic use beyond type 2 diabetes. However, be- or 30 mg/kg to ICR mice inhibited 11b-HSD1 reduc- cause of the nonselective nature of carbenoxolone, tase activity at 1 h by 60% and 75%, respectively. these clinical findings should be interpreted with cau- Compound 544 was studied in murine models of tion and remain to be validated with selective diet-induced obesity (DIO), type 2 diabetes and apoli- 11b-HSD1 inhibitors. However, these studies are poprotein E (apoE) KO, mouse model of atheroscle- termed as “Proof-of-concept” experiments since they rosis. Oral administration of this compound (20 mg/kg, have prompted several pharmaceutical companies to bid.) lowered body weight (7%), food intake (12.1%), develop selective 11b-HSD1 inhibitors. fasting glucose (15%), insulin, triglycerides and cho- Emodin, an anthraquinone derivative, is a potent lesterol in DIO mice after 11 days of treatment. In and selective 11b-HSD1 inhibitor with the IC50 of 186 HF-STZ model, compound 544 (30 mg/kg, bid po) and 86 nM for human and mouse 11b-HSD1, respec- markedly lowered fasting glucose and decreased se- tively. In diet induced obese mice, oral administration rum glucose excursions in OGTT experiments after of emodin improved insulin sensitivity and lipid me- 9 days of treatment. In apoE KO mouse model, com- tabolism, and lowered blood glucose and hepatic pound 544 (10 mg/kg/day) almost completely pre- PEPCK, and G6Pase mRNA [18]. vented plaque formation during 8 weeks of dosing. In the same animal model, a modest decrease in post- prandial glucose levels was observed while body Arylsulfonamidothiazole based inhibitors from weight remained unchanged. SAR studies reveled Biovitrum more potent and selective 11b-HSD1 inhibitor (com- pound 38) which exhibited sustained inhibition in PD Biovitrum identified arylsulfonamidothiazoles as se- assay up to 16 h, had excellent pharmacokinetics lective inhibitors using a high-throughput screen of an properties across various species with low clearance in-house compound library. Lead optimization fur- [8]. Compound 38 in combination with rosiglitazone nished two compounds, viz. BVT-14225 and BVT- (PPARg agonist) was shown to decrease hepatic stea- 2733 as examples of arylsulfonamidothiazole class tosis and serum TAG levels as compared to rosiglita- [4]. BVT2733 was more potent for the mouse enzyme zone treatment alone [7]. MK-0916 and MK-0736 are with IC50 = 96 ± 14 nM while BVT14225 was more two 11b-HSD1 inhibitors that have been developed as potent for the human enzyme with IC50 = 52 ± 3 nM. potential treatments for hyperglycemia, hypertension, Both the compounds have around 200-fold selectivity and other metabolic syndrome components. A phase I against 11b-HSD2 enzyme (IC50 = 10 µM), and showed pharmacodynamic study has shown that the dosages dose-dependent reduction in glucose levels and de- of 2 and 7 mg/day MK-0736 inhibit hepatic 11b- creased hepatic glucose production after repeated HSD1 by about 85% and 95%, respectively, and that dose treatment in hyperglycemic KKAy mice. The first 2 mg/day MK-0736 and 6 mg/day MK-0916 are ap- selective 11b-HSD1 inhibitor that was tested in clinical proximately equipotent with respect to inhibition of trials was BVT3498 (AMG-331), which was later ter- hepatic 11b-HSD1 [17, 48]. minated [21]. Recently, an adipose selective 11b- HSD1 inhibitor T-BVT was derived from BVT- 2733, using a peptide connector CKGGRAKDC, that homes Piperazine sulfonamide and benzenesulfonamides to white fat vasculature [31]. This novel drug im- based inhibitors from Wyeth proved glucose tolerance, was able to resist dietary weight gain, and increased adiponectin, leptin, vis- Wyeth identified piperazine sulfonamide based lead fatin and vaspin, in DIO C57BL/6J mice model sys- compound as a dual potent and selective inhibitor of tem [31]. In addition, T-BVT treatment decreased the human-11b-HSD1 with IC50 of 61 nM [60]. They have expression of PEPCK and increased the expression of also reported the synthesis and biological activity of mCPT-I and PPARa in liver. novel potent and selective 2,4-disubsituted benzenesul-
1060 Pharmacological Reports, 2012, 64, 10551065 11ß-hydroxysteroid dehydrogenase 1 in metabolic syndrome Amit Joharapurkar et al.
fonamides [59]. This class of compounds showed metabolic drugs is reported in many patent ap- good potency against human and mouse 11b-HSD1 plications [9]. These rational combinations are believed and displayed good pharmacokinetics in mice and ro- to be complimentary or additive in nature. In animals, bust inhibition of 11b-HSD1 in the liver and fat. peroxisome proliferator-activated receptor-a (PPARa) and PPARg agonists down-regulate 11b-HSD1 mRNA Pyridyl sulfonamide based inhibitors from Pfizer and activity in liver and adipose tissue, respectively, and PPARg agonists reduce ACTH secretion from Pfizer identified PF-915275, a pyridyl sulfonamide, corticotrophs [56]. Additive action of 11b-HSD1 inhi- as a potent and selective inhibitor of 11b-HSD1 [50]. bition and PPAR-g agonism on hepatic steatosis and When assayed for its potential to inhibit purified re- triglyceridemia in diet-induced obese rats was re- combinant 11b-HSD1 in a biochemical assay, PF-915275 cently reported [7]. Since both the approches reduce proved to be a much more potent inhibitor of the hu- liver and plasma lipids in rodents through partly dis- man subtype compared with the mouse enzyme. tinct mechanisms, combination of these two agents PF-915275 was effective in inhibiting 11b- HSD1 me- additively reduce liver steatosis and triglyceridemia. diated conversion of prednisone to prednisolone, when Phase II clinical trial of INCB13739 involved evalua- administered to cynomolgus monkeys. After 4 h treat- tion of the compound in combination with metformin ment with PF-915275 in cynomolgus monkeys, reduc- in patients with type 2 diabetes whose glucose levels tion in insulin levels were observed. When adminis- were not adequately controlled by metformin alone. tered to 6 healthy adult humans for 14 days, it was After 12 days of treatment, the combination treatment found to be safe and well tolerated at a range of doses group had lower glycosylated hemoglobin (HbA1c), and did not affect HPA axis biomarkers [12]. total plasma cholesterol, and improved insulin sensi- tivity compared with the metformin treatment alone. Table 2 summarizes the key developments in 11b-HSD1 Piperidine carboxamides based inhibitors from Incyte inhibitor area.
Incyte Corporation has disclosed piperidine carbox- amides represented by compound 62 as highly potent 11b-HSD1 inhibitors. The lead candidate, INCB13739, Key issues with the development of is advanced in clinical trials up to phase IIb [41]. 11b-HSD1 inhibitors: isoform and tissue INCB13739 is highly potent (human 11b-HSD1, IC50 selectivity = 1.1 nM) and shows 1000-fold selectivity against 11b-HSD2. When administered orally to subjects One of the concerns about 11b-HSD1 inhibitors is with type 2 diabetes mellitus, INCB13739 improved their potential effect on circulating glucocorticoid hepatic insulin sensitivity and increased peripheral levels and therefore the negative feedback system insulin-stimulated glucose uptake as compared to pla- within the HPA axis. Glucocorticoids (cortisol and cebo. Reduction in plasma cholesterol and LDL levels cortisone in human) are synthesized in and secreted were the other beneficial effects. The compound ap- from the zona fasciculata of the adrenal gland, under peared to be well tolerated without any major side ef- control of adrenocorticotropic hormone (ACTH, also fects and no instances of rebound hypoglycemia. known as corticotropin), which is secreted from the There was a modest increase in morning adrenocorti- anterior pituitary gland. The secretion of ACTH, in cotropic hormone (ACTH) levels with treatment. turn, is regulated by vasopressin and corticotropin- However, serum cortisol was not increased, which in- releasing hormone (CRH), both peptide hormones dicated minimal effect on HPA axis. that originate in the hypothalamus. This complex set of hormone interactions and regulations is often re- 11b-HSD1 inhibitors and combination ferred to as the hypothalamus-pituitary-adrenal (HPA) with other metabolically active drugs axis, which consists of negative feedback circuitry to the pituitary and hypothalamus. Combination of 11b-HSD1 inhibitors with antidiabet- The reduction in cortisol caused by 11b-HSD1 in- ics, antihypertensives, antiobesity compounds like hibitors might decrease feedback inhibition in brain, cannabinoid receptor type 1 antagonists, and other which may cause activation of the HPA axis with in-
Pharmacological Reports, 2012, 64, 10551065 1061 creased cortisol synthesis in the adrenal. The potential in 11b-HSD1–/– mice with complementation (rescue) adverse effects linked to upregulation of the HPA axis of the enzyme solely in the liver [38] suggest that this are manifested in patients who have Cushing’s syn- may not be effective. The lesson from the drome, and are exemplified by osteoporosis, immuno- 11b-HSD1–/– mice is that despite modest activation suppression, hypertension and glucose intolerance of the HPA axis, levels of glucocorticoids inside key [6]. Despite this theoretical predictions for hyperten- metabolic and CNS cells are reduced. Crucially, the sion by 11b-HSD1 inhibitors, there are no changes in HPA axis forward drive apparently remains intact at the phase I studies [12] and limited reversible ACTH times of stress, preventing glucocorticoid insuffi- increases in the phase II studies [54], indicating that ciency. Whether or not the increase in ACTH with advanced phase III studies will eventually assess this 11b-HSD1 deficiency [22] triggers increased adrenal possibility. In fact, recent report suggests that MK- and androgen production can only be satisfactorily 0736 was well tolerated and did appear to modestly answered in humans, since the rodent adrenal cortex improve other BP (blood pressure) endpoints in does not synthesize such steroids. Potentially, how- overweight-to-obese hypertensive patients [48]. As ever, by analogy to CRD, hirsutism may be an adverse anticipated, there were significant, dose-dependent in- effect of clinical 11b-HSD1 inhibition. Finally, since creases in circulating adrenal androgens in patients circulating cortisol production undergoes a pro- treated with MK-0736 and MK-0916, however, the nounced circadian rhythm, when free cortisol levels increases in androgens observed in this study were not exceed the levels required for substantial GR activa- clinically meaningful, as individual androgen levels tion in a particular tissue, 11b-HSD1 inhibition may were never found to exceed two-fold the upper limit have only minimal effects on GR responsive gene tar- of normal. gets. It is therefore possible that a specific dosing Several natural product derivatives, including strategy may be necessary to overcome this and that carbenoxolone, glycyrrhetinic acid, metyrapone and inhibition in humans may have less impact than seen ketoconazole have been shown to exhibit inhibitory in rodents with their differing physiology and energy activity against 11b-HSDs. However, none is fully se- economy. The advancement of numerous structural lective for 11b-HSD1. Inhibition of 11b-HSD2 pro- classes of selective 11b-HSD1 inhibitors further indi- duces apparent mineralocorticoid excess, an undesir- cates that more refined design and screening for iso- able effect. Pharmacophore modeling and a variety of form and tissue selectivity would yield potential screening approaches have revealed many small therapeutics in this area. molecules that selectively inhibit 11b-HSD1 but not 2 [45], perhaps reflecting the minor sequence identity between HSD11B1 and HSD11B2. In addition to 11b-HSD2, other enzymes of SDR family also share Conclusion high homology with 11b-HSD1. It is highly important to avoid potential adverse effects by cross-inhibition of these enzymes. For example, inhibition of the re- Since glucocorticoids control a large array of meta- lated 17b-HSDs may cause abnormalities since it con- bolic and biochemical pathways, it is obvious that trols key sex steroid metabolism [49]. proposed applications of 11b-HSD1 inhibitors range The major concern for clinical development of from insulin resistance, type 2 diabetes, obesity and 11b-HSD1 inhibitors is whether such tissue-specific related metabolic disturbances to cognitive impair- dysregulation occurs in obese patients with type 2 dia- ments, glaucoma, muscle atrophy and osteoporosis. betes, and this is most crucial because despite display- Thus, it may be predicted that for different therapeutic ing good potency in preclinical studies, 11b-HSD1 in- applications, distinct classes of inhibitors with various hibitors did not advance much beyond phase II clini- pharmacokinetic parameters and tissue-penetration/ cal studies in patients with type 2 diabetes [10, 21]. specificity might be required. In addition to that, the Probably the key metabolic tissue for 11b-HSD1 inhi- combination of 11b-HSD1 inhibitors with other drugs bition is adipose, whereas benefits of the inhibition of targeting metabolic syndrome would be interesting 11b-HSD1 in liver are a matter of uncertainty. In ad- approach. This represents a sensible trend to multifac- dition, limited penetration through blood-brain barrier torial and pathogenically complex disorders, recog- could be potentially beneficial for stabilization of ‘co- nizing the combination therapy approach for treating mpensatory’ HPA axis activation [22, 28]. Recent data a combination disorder like metabolic syndrome.
1062 Pharmacological Reports, 2012, 64, 10551065 11ß-hydroxysteroid dehydrogenase 1 in metabolic syndrome Amit Joharapurkar et al.
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