Synthesis and biological evaluation of 3-aryl-3-(4-phenoxy)-propionic acid as a novel series of G protein-coupled receptor 40 agonists.
High-throughput screening of a subset of the J&J compound library containing the carboxylic acid functional group uncovered a bromophenyl derivative as a moderate potent GPR40 agonist. Chemical elaboration of this bromophenyl led to the discovery of a novel series of GPR40 agonists with submicromolar potency. Among them, 22 and 24 behaved as full agonists when compared to the endogenous GPR40 ligand linolenic acid in a functional Ca+2 flux assay in HEK cells expressing GPR40 receptor. Several GPR40 agonists have also demonstrated the ability to induce glucose-mediated insulin secretion in the mouse MIN6 pancreatic beta-cell line. Our data supports the hypothesis that GPR40 may play an important role in fatty acid-mediated glucose-dependent insulin secretion. Compound 22 exhibited good pharmacokinetic profile in rat and may serve as a good candidate for in vivo study and may help to determine if GPR40 agonists would be beneficial in the treatment of type II diabetes.
Song
Fengbin
F
Drug Discovery Division, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 8 Clarke Drive, Cranbury, New Jersey 08512, USA.
Lu
Songfeng
S
Gunnet
Joe
J
Xu
Jun Z
JZ
Wines
Pam
P
Proost
Jef
J
Liang
Yin
Y
Baumann
Chris
C
Lenhard
Jim
J
Murray
William V
WV
Demarest
Keith T
KT
Kuo
Gee-Hong
GH
D000818:Animals; D001682:Biological Availability; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C521966:3-(4-(methylbutoxy)phenyl)-3-phenylpropionic acid; C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; D007328:Insulin; D010666:Phenylpropionates; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D002118:Calcium