Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold.
نویسندگان
چکیده
Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, LogD, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.
منابع مشابه
Chronic treatment with novel GPR40 agonists improve whole-body glucose metabolism based on the glucose-dependent insulin secretion.
GPR40 is a free fatty acid receptor that has been shown to regulate glucose-dependent insulin secretion. This study aimed to discover novel GPR40 agonists and investigate the whole-body effect on glucose metabolism of GPR40 activation using these novel GPR40 agonists. To identify novel GPR40-specific agonists, we conducted high-throughput chemical compound screening and evaluated glucose-depend...
متن کاملSynthesis and docking study on thiadiazolo[3,2-a][1,3]diazepin-8(5H)-one derivatives as selective GABA(A) agonists
HIE-124 is a new member of ultra-short acting hypnotics’ drug family. In this research, the synthesis ofanalogues of HIE-124 drug in the heterocyclic thiazole ring replaced to thiadiazole, will be presented.Thiadiazolodiazepines during a two-step reaction starting from the amino thiadiazole resultedfrom-various derivatives of benzoic acid and thiosemicarbazide were synthesized. In the first ste...
متن کاملGPR40: a therapeutic target for mediating insulin secretion (review).
G-protein-coupled receptor 40 (GPR40), known as free fatty acid receptor 1, is mainly expressed in pancreatic β-cells and activated by medium- and long-chain fatty acids. Increasing evidence indicates that the activation of GPR40 in cells causes insulin secretion, and GPR40 has become an attractive therapeutic target for type 2 diabetes. Recently, certain novel GPR40 agonists have been identifi...
متن کاملUncovering the Pharmacology of the G Protein-Coupled Receptor GPR40: High Apparent Constitutive Activity in Guanosine 5 -O-(3-[S]thio)triphosphate Binding Studies Reflects Binding of an Endogenous Agonist
In cells lacking expression of Ca -mobilizing G proteins, coexpression of human GPR40 and G q allowed mediumand long-chain fatty acids to elevate intracellular [Ca ]. This was also observed when human embryonic kidney (HEK) 293 cells were transfected with a GPR40-G q fusion protein. The kinetic of elevation of intracellular [Ca ] slowed with increasing fatty acid chain length, suggesting differ...
متن کاملAnti-Helicobacter pylori activity and Structure-Activity Relationship study of 2-Alkylthio-5-(nitroaryl)-1,3,4-thiadiazole Derivatives
Nitro-containing heteroaromatic derivatives structurally related to nitroimidazole (Metronidazole) are being extensively evaluated against Helicobacter pylori isolates. On the other hand, 1,3,4-thiadiazole derivatives have also demonstrated promising antibacterial potential. In present study, we evaluated anti-H. pylori activity of novel hybrid molecules bearing nitroaryl and 1,3,4-thiadiazole ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Bioorganic & medicinal chemistry
دوره 24 13 شماره
صفحات -
تاریخ انتشار 2016