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. 2019 Jul 15;29(14):1842-1848.
doi: 10.1016/j.bmcl.2019.04.050. Epub 2019 May 2.

Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs

Barbara Pio  1 , Harry R Chobanian  2 , Yan Guo  2 , Hubert Josien  2 , William K Hagmann  2 , Michael Miller  2 , Maria E Trujillo  3 , Melissa Kirkland  3 , Daniel Kosinski  3 , Joel Mane  3 , Michele Pachanski  3 , Boonlert Cheewatrakoolpong  3 , Eric Ashley  4 , Robert Orr  4 , Michael J Wright  5 , Randal Bugianesi  5 , Sarah Souza  5 , Xiaoping Zhang  5 , Jerry Di Salvo  5 , Adam B Weinglass  5 , Richard Tschirret-Guth  6 , Koppara Samuel  6 , Qing Chen  6 , Jackie Shang  6 , James Lamca  6 , Juliann Ehrhart  7 , Ravi Nargund  2 , Andrew D Howard  3 , Steven L Colletti  2
Affiliations

Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs

Barbara Pio et al. Bioorg Med Chem Lett. .

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.

Keywords: Diabetes; FFA1; GPCR; GPR40 AgoPAM; Indane.

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