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Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs.

Authors :
Pio B
Chobanian HR
Guo Y
Josien H
Hagmann WK
Miller M
Trujillo ME
Kirkland M
Kosinski D
Mane J
Pachanski M
Cheewatrakoolpong B
Ashley E
Orr R
Wright MJ
Bugianesi R
Souza S
Zhang X
Di Salvo J
Weinglass AB
Tschirret-Guth R
Samuel K
Chen Q
Shang J
Lamca J
Ehrhart J
Nargund R
Howard AD
Colletti SL
Source :
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Jul 15; Vol. 29 (14), pp. 1842-1848. Date of Electronic Publication: 2019 May 02.
Publication Year :
2019

Abstract

GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet β-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM). Efforts were made to identify a suitable GPR40 AgoPAM tool molecule to investigate mechanism of action and de-risk liver toxicity of GPR40 AgoPAMs due to reactive acyl-glucuronide (AG) metabolites.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Details

Language :
English
ISSN :
1464-3405
Volume :
29
Issue :
14
Database :
MEDLINE
Journal :
Bioorganic & medicinal chemistry letters
Publication Type :
Academic Journal
Accession number :
31109791
Full Text :
https://doi.org/10.1016/j.bmcl.2019.04.050