Abstract
A current trend in the quest for new therapies for complex, multifactorial diseases, such as diabetes mellitus (DM), is to find dual or even multi-target inhibitors. In DM, the sodium dependent glucose cotransporter 2 (SGLT2) in the kidneys and the glycogen phosphorylase (GP) in the liver are validated targets. Several (β-D-glucopyranosylaryl)methyl (het)arene type compounds, called gliflozins, are marketed drugs that target SGLT2. For GP, low nanomolar glucose analogue inhibitors exist. The purpose of this study was to identify dual acting compounds which inhibit both SGLTs and GP. To this end, we have extended the structure-activity relationships of SGLT2 and GP inhibitors to scarcely known (C-β-D-glucopyranosylhetaryl)methyl arene type compounds and studied several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitors against SGLT. New compounds, such as 5-arylmethyl-3-(β-D-glucopyranosyl)-1,2,4-oxadiazoles, 5-arylmethyl-2-(β-D-glucopyranosyl)-1,3,4-oxadiazoles, 4-arylmethyl-2-(β-D-glucopyranosyl)pyrimidines and 4(5)-benzyl-2-(β-D-glucopyranosyl)imidazole were prepared by adapting our previous synthetic methods. None of the studied compounds exhibited cytotoxicity and all of them were assayed for their SGLT1 and 2 inhibitory potentials in a SGLT-overexpressing TSA201 cell system. GP inhibition was also determined by known methods. Several newly synthesized (C-β-D-glucopyranosylhetaryl)methyl arene derivatives had low micromolar SGLT2 inhibitory activity; however, none of these compounds inhibited GP. On the other hand, several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitor compounds with low micromolar efficacy against SGLT2 were identified. The best dual inhibitor, 2-(β-D-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole, had a Ki of 31 nM for GP and IC50 of 3.5 μM for SGLT2. This first example of an SGLT-GP dual inhibitor can prospectively be developed into even more efficient dual-target compounds with potential applications in future antidiabetic therapy.
Highlights
Diabetes mellitus (DM) is a highly prevalent disease, affecting an estimated 9.3%of the adult population worldwide [1]
The synthesis of 5-arylmethyl-3-(β-D-glucopyranosyl)-1,2,4-oxadiazoles was accomplished by adaptation of a published procedure [57,58]
The preparation of 4-arylmethyl-2-(β-D-glucopyranosyl)pyrimidines was envisaged by base-mediated cyclocondensations of 14
Summary
Diabetes mellitus (DM) is a highly prevalent disease, affecting an estimated 9.3%of the adult population worldwide [1]. Diabetes mellitus (DM) is a highly prevalent disease, affecting an estimated 9.3%. More than 463 million adults have diabetes and 352 million of them are middle-aged working people. In 2019, more than 50% of the population had undiagnosed diabetes [1]. Diabetics have an increased risk of complications, 4.0/). Pharmaceuticals 2021, 14, 364 including retinopathy, blindness, kidney failure, cardiovascular disease, neuropathy, stroke, and loss of toes, feet, or legs. Type 2 diabetes (non-insulin-dependent or T2DM) is a chronic disease characterized by hyperglycaemia resulting from defects in insulin secretion and/or action and increased hepatic glucose output [2,3]. More than 90% of diabetic patients have T2DM. In the absence of a causal cure, the management of T2DM is focused on lowering blood glucose levels to prevent and delay the onset of diabetic complications. Glycaemic control is often difficult to achieve with oral antidiabetic agents [4]
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