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Medchem & Toxicology 2018
Page 91
Journal of Organic & Inorganic Chemistry
ISSN: 2472-1123
A n n u a l C o n g r e s s o n
Medicinal Chemistry,
Pharmacology and toxicology
J u l y 3 0 - 3 1 , 2 0 1 8
Am s t e r d a m , N e t h e r l a n d s
T
GR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and
modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent and selective TGR5 agonist
(hTGR5 EC
50
= 57 pM, mTGR5 = 62 pM) with a favourable pharmacokinetic profile. The compound 6g was found to have potent
glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED50 of 7.9 mg/kg and ED90 of 29.2
mg/kg. GPR40 / FFAR1 is another G protein-coupled receptors predominantly expressed in pancreatic β-cells and activated
by long-chain free fatty acids, mediates enhancement of glucose-stimulated insulin secretion. A series of novel substituted
3-(4-aryloxyaryl) propanoic acid derivatives were prepared and evaluated for their activities as GPR40 agonists, leading to the
identification of compound 5, which is highly potent in vitro assays and exhibits robust glucose lowering effects during an oral
glucose tolerance test in nSTZ rats (ED50 = 0.8 mg/kg; ED90 = 3.1 mg/kg) with excellent pharmacokinetic profile, and devoid of
cytochromes P450 isoforms inhibitory activity.
sameeragarwal@zyduscadila.com sameer_ag@yahoo.comDiscovery of novel anti-diabetic agents
Sameer Agarwal
Zydus Research Centre, Cadila Healthcare Ltd., Indian
J Org Inorg Chem 2018, Volume 4
DOI: 10.21767/2472-1123-C3-009
In vivo efficacy of 6g (TGR5 agonist) in DIO C57 mice
In vivo efficacy studies of 5 (GPR40 agonist) in nSTZ wistar rats