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 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.
Wang
Yingcai
Y
Department of Chemistry, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. yingcaiw@amgen.com
Jiao
Xianyun
X
Kayser
Frank
F
Liu
Jiwen
J
Wang
Zhongyu
Z
Wanska
Malgorzata
M
Greenberg
Joanne
J
Weiszmann
Jennifer
J
Ge
Hongfei
H
Tian
Hui
H
Wong
Simon
S
Schwandner
Ralf
R
Lee
Taeweon
T
Li
Yang
Y
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
D000081:Acetamides; D000242:Cyclic AMP; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C473103:FFAR2 protein, human; C506481:Ffar2 protein, mouse