title: The first synthetic agonists of FFA2: Discovery and SAR of phenylacetamides as allosteric modulators.
abstract: 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.
authors.affiliation: Department of Chemistry, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. yingcaiw@amgen.com
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Wang
authors.forename: Xianyun
authors.initials: X
authors.lastname: Jiao
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
authors.forename: Jiwen
authors.initials: J
authors.lastname: Liu
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Wang
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wanska
authors.forename: Joanne
authors.initials: J
authors.lastname: Greenberg
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.forename: Hongfei
authors.initials: H
authors.lastname: Ge
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.forename: Simon
authors.initials: S
authors.lastname: Wong
authors.forename: Ralf
authors.initials: R
authors.lastname: Schwandner
authors.forename: Taeweon
authors.initials: T
authors.lastname: Lee
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000494:Allosteric Regulation; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000242:Cyclic AMP; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C473103:FFAR2 protein, human; C506481:Ffar2 protein, mouse