Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs

  • Bioorg Med Chem Lett. 2019 Jul 15;29(14):1842-1848. doi: 10.1016/j.bmcl.2019.04.050.
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
  • 1. Discovery Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: [email protected].
  • 2. Discovery Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 3. In Vivo Pharmacology, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 4. Process Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 5. In Vitro Pharmacology, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 6. Drug Metabolism and Pharmacokinetics, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 7. SALAR Discovery, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
PMID: 31109791 DOI: 10.1016/j.bmcl.2019.04.050
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.