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Natural Products As Lead Compounds for Sodium Glucose Cotransporter (SGLT) Inhibitors

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Natural Products As Lead Compounds for Sodium Glucose Cotransporter (SGLT) Inhibitors Reviews Natural Products as Lead Compounds for Sodium Glucose Cotransporter (SGLT) Inhibitors Author ABSTRACT Wolfgang Blaschek Glucose homeostasis is maintained by antagonistic hormones such as insulin and glucagon as well as by regulation of glu- Affiliation cose absorption, gluconeogenesis, biosynthesis and mobiliza- Formerly: Institute of Pharmacy, Department of Pharmaceu- tion of glycogen, glucose consumption in all tissues and glo- tical Biology, Christian-Albrechts-University of Kiel, Kiel, merular filtration, and reabsorption of glucose in the kidneys. Germany Glucose enters or leaves cells mainly with the help of two membrane integrated transporters belonging either to the Key words family of facilitative glucose transporters (GLUTs) or to the Malus domestica, Rosaceae, Phlorizin, flavonoids, family of sodium glucose cotransporters (SGLTs). The intesti- ‑ SGLT inhibitors, gliflozins, diabetes nal glucose absorption by endothelial cells is managed by SGLT1, the transfer from them to the blood by GLUT2. In the received February 9, 2017 kidney SGLT2 and SGLT1 are responsible for reabsorption of revised March 3, 2017 filtered glucose from the primary urine, and GLUT2 and accepted March 6, 2017 GLUT1 enable the transport of glucose from epithelial cells Bibliography back into the blood stream. DOI http://dx.doi.org/10.1055/s-0043-106050 The flavonoid phlorizin was isolated from the bark of apple Published online April 10, 2017 | Planta Med 2017; 83: 985– trees and shown to cause glucosuria. Phlorizin is an inhibitor 993 © Georg Thieme Verlag KG Stuttgart · New York | of SGLT1 and SGLT2. With phlorizin as lead compound, specif- ISSN 0032‑0943 ic inhibitors of SGLT2 were developed in the last decade and some of them have been approved for treatment mainly of Correspondence type 2 diabetes. Inhibition of SGLT2 eliminates excess glucose Prof. Dr. Wolfgang Blaschek via the urine. In recent times, the dual SGLT1/SGLT2 inhibitory Vogteiweg 13 B, 24119 Kronshagen, Germany activity of phlorizin has served as a model for the develop- Phone:+49431583498 ment and testing of new drugs exhibiting both activities. [email protected] Besides phlorizin, also some other flavonoids and especially flavonoid enriched plant extracts have been investigated for their potency to reduce postprandial blood glucose levels which can be helpful in the prevention and supplementary treatment especially of type 2 diabetes. minded of extracts of the bark from cinchona and willow trees, The History of Phlorizin and originally were thought to have antipyretic properties and might be used in the treatment of fevers and infectious diseases, In 1835 a bitter tasting compound was isolated from the bark of especially malaria [3]. Then, in 1886, it was described that phlo- apple trees and named phloridzin (later most commonly called rizin given in high doses of more than 1.0g causes glucosuria in phlorizin, but also phlorrhizin, phlorhizin, or phlorizoside) [1]. humans [4]. At these days, diabetes mellitus also causing glucosu- Thenamephloridzin(inGreek:φλοιός =bark,ρίζα =root)wascho- ria was considered to be a structural disease of the kidneys. Later sen as higher concentrations of the compound were found in the on, by further studies with phlorizin, it was concluded that glyco- root bark compared to the stem bark. More than 100 years later, suria, polyuria, and weight loss caused by phlorizin in animals is in 1942, the complete structure of phlorizin was determined by the equivalent to human diabetes and phlorizin became one of total synthesis [2]. Phlorizin was shown to be a flavonoid, more the main instruments to study this human disorder and the func- precisely the 2′-glucoside of phloretin, a dihydrochalcone (chem- tion of the kidneys [5]. By intravenous administration of phlorizin ical name: 1-[2-(β-D-glucopyranosyloxy)-4,6-dihydroxyphenyl]-3- to healthy people, the measurement of the glomerular filtration (4-hydroxyphenyl)-1-propanone; ▶ Fig. 1). Due to their bitter fla- rate for glucose in the kidney became possible in the 1930s [6]. vor, the phlorizin containing extracts of the bark of apple trees re- Some decades later, it could be shown that intestinal glucose ab- Blaschek W. Natural Products as … Planta Med 2017; 83: 985–993 985 Reviews sorption is done by sodium-glucose cotransport [7] and that phlorizin inhibits the transport of glucose in the small intestine [8]. Then it was described that the renal reabsorption of glucose in the kidney is located in the luminal membrane of brush border cells of the proximal part of the tubulus [9]. Finally, investigations on the inhibition of sugar transport across membranes with the help of phlorizin led to the identification of the coupled sodium- glucose transport mechanism [10]. The detailed characterization of the so-called sodium glucose cotransporters (SGLTs) followed [11] and their potential inhibition became more and more inter- esting for the treatment of diabetes. Phlorizin could be shown to be a potent inhibitor of both known SGLTs for glucose transport: the intestinal SGLT-1 responsi- ble for the absorption of glucose from the small intestine, and SGLT-2 and SGLT-1 responsible together for the reabsorption of glucose from the primary urine in the kidney. Phlorizin, however, had some disadvantages for the use in therapy of diabetes. Phlo- rizin inhibits both SGLTs with low therapeutic selectivity, it is poorly absorbed in the small intestine, and it is effectively hydro- lyzed by intestinal lactase (LPH = lactose-phlorizin-hydrolase) re- ▶ Fig. 1 Chemical structures of the natural product phlorizin as lead sulting in low oral bioavailability and the aglycon phloretin as hy- compound for the synthetic O-glucoside analogs T-1095 (methyl drolysis product is an inhibitor of the ubiquitous glucose trans- carbonate as prodrug), sergliflozin etabonate and remogliflozin porter GLUT1 obstructing glucose uptake into various tissues etabonate (etabonates as prodrugs), and for the C-glucoside ana- [12]. Nevertheless, phlorizin was and is the lead compound for logs dapagliflozin, canagliflozin, empagliflozin and sotagliflozin. the development of synthetic analogs with improved bioavailabil- ity, stability, and selectivity for SGLT2 and investigations on the use of phlorizin, including food products for an additional treat- ment of diabetes and obesity, again are of interest. First some O- Diabetes mellitus: Disease, Epidemiology, glucoside analogs of phlorizin were synthesized and tested. The Diagnosis and Medications orally available STLT-2-inhibitor T-1095 (▶ Fig. 1) developed at the end of the last century had a better selectivity for SGLT-2 with Diabetes mellitus (DM), shortly named diabetes, is a serious, an IC50 of 200 nM against SGLT-1 and 50 nM against SGLT-2 [13]. chronic, metabolic disease with high blood sugar levels over a pro- Other O-glucoside analogs developed later, in the first decade of longed period of time. Hyperglycemia results from inadequate in- this century, were sergliflozin [14] or remogliflozin [15] (▶ Fig. 1). sulin secretion, insulin resistance, or excessive glucagon secretion. The disadvantages of all these O-glucoside analogs of phlorizin Typical first symptoms of diabetes are frequent urination and in- still were a poor pharmacokinetic stability and an insufficient se- creased thirst. Long term problems of diabetes mainly result from lectivity for SGLT2. A method for the synthesis of C-glycoside ana- damages in small blood vessels and include cardiovascular dis- logs of phlorizin was first described in 2000 [16] and some years eases such as stroke and heart attack, chronic kidney failure later, in 2008, the discovery of dapagliflozin (▶ Fig. 1), a C-glyco- (diabetic nephropathy), peripheral neuropathy, and vascular dis- side analog with high SGLT2 selectivity, was published [17]. Dapa- eases like foot ulcers and eye damage (diabetic retinopathy). gliflozin was approved for the treatment of diabetes type 2 in Eu- Three main types of diabetes are known [26, 27]: rope in 2012 and in the USA in 2014. Development, approval, and Type 1 diabetes mellitus (T1DM) is caused by insufficient up to marketing of other C-glycoside analogs of phlorizin like canagliflo- no more production of insulin in the beta cells of the islets of Lan- zin (▶ Fig. 1; approval EU/USA in 2013) [18] and empagliflozin gerhans in the pancreas due to a T-cell-mediated autoimmune at- (▶ Fig. 1; approval EU/USA in 2014) [19] with a high SGLT2-selec- tack against beta cells, and consequently it is an immune-mediat- tivity for the treatment of diabetes type 2 followed in the last ed disease. Therefore, most cases of T1DM are seen in children years and intensive research in this field is going on. Other gliflo- and young people (insulin dependent diabetes). zins like ipragliflozin, luseogliflozin, and tofogliflozin have been Type 2 diabetes mellitus (T2DM) begins with a decreased re- approved in Japan [20] and the research for new gliflozins is going spond of the cells of many body-tissues to insulin (insulin resis- on. Nowadays, also the interest in combined SGLT2/SGLT1-inhib- tance), resulting in a permanent increase in insulin production by itors is growing continuously. Compounds such as sotagliflozin pancreatic beta cells until their exhaustion. Finally also a lack of in- (▶ Fig. 1) are thought to be applied also together with insulin in sulin is developing. T2DM is rather characteristic for adult and therapy of type 1 diabetes [21]. obese people and often develops gradually. In the following, some aspects of this historical outline will be Gestational diabetes can develop in pregnant women (inci- discussed more in detail. In this context, also some readable re- dence 2–10%) without previous high blood sugar levels. Concern- views published in the last few years should be mentioned [20, ing an insufficient responsiveness of body cells to insulin and an 22–25]. inadequate insulin secretion, gestational diabetes resembles 986 Blaschek W. Natural Products as … Planta Med 2017; 83: 985–993 T2DM. Gestational diabetes often disappears (about 95% of wom- tissues. Sulfonylureas (e.g., chlorpropamide, glimepiride, glipi- en) after pregnancy.
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