The first synthetic agonists of FFA2: Discovery and SAR of phenylacetamides as allosteric modulators

Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor for which only short-chain fatty acids (SCFAs) have been reported as endogenous ligands. We describe the discovery and optimization of phenylacetamides as allosteric agonists of FFA2. These novel ligands can suppress adipocyte lipolys...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-01, Vol.20 (2), p.493-498
Hauptverfasser:	Wang, Yingcai, Jiao, Xianyun, Kayser, Frank, Liu, Jiwen, Wang, Zhongyu, Wanska, Malgorzata, Greenberg, Joanne, Weiszmann, Jennifer, Ge, Hongfei, Tian, Hui, Wong, Simon, Schwandner, Ralf, Lee, Taeweon, Li, Yang
Format:	Artikel
Sprache:	eng
Schlagworte:	Acetamides - chemical synthesis Acetamides - chemistry Acetamides - pharmacokinetics Agonist Allosteric Allosteric Regulation Animals Biological and medical sciences Cyclic AMP - metabolism Drug Discovery FFA2 General and cellular metabolism. Vitamins GPR43 Humans Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Pharmacology. Drug treatments Phenylacetamide Rats Receptors, Cell Surface - agonists Receptors, Cell Surface - metabolism Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - metabolism Structure-Activity Relationship
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Zusammenfassung:	Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor for which only short-chain fatty acids (SCFAs) have been reported as endogenous ligands. We describe the discovery and optimization of phenylacetamides as allosteric agonists of FFA2. These novel ligands can suppress adipocyte lipolysis in vitro and reduce plasma FFA levels in vivo, suggesting that these allosteric modulators can serve as pharmacological tools for exploring the potential function of FFA2 in various disease conditions. Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor for which only short-chain fatty acids (SCFAs) have been reported as endogenous ligands. We describe the discovery and optimization of phenylacetamides as allosteric agonists of FFA2. These novel ligands can suppress adipocyte lipolysis in vitro and reduce plasma FFA levels in vivo, suggesting that these allosteric modulators can serve as pharmacological tools for exploring the potential function of FFA2 in various disease conditions.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.11.112