2-Substituted piperazine-derived imidazole carboxamides as potent and selective CCK1R agonists for the treatment of obesity.
The discovery and structure-activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.
Berger
Richard
R
Department of Medicinal Chemistry, Merck & Co., Inc., 126 East Lincoln Ave., PO Box 2000, Rahway, NJ 07065-0900, USA.
Zhu
Cheng
C
Hansen
Alexa R
AR
Harper
Bart
B
Chen
Zhesheng
Z
Holt
Tom G
TG
Hubert
James
J
Lee
Susan J
SJ
Pan
Jie
J
Qian
Su
S
Reitman
Marc L
ML
Strack
Alison M
AM
Weingarth
Drew T
DT
Wolff
Michael
M
Macneil
Douglas J
DJ
Weber
Ann E
AE
Edmondson
Scott D
SD
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019742:Chemokines, CC; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D043886:Receptor, Cholecystokinin A / Q000819:agonists*; D011949:Receptors, Cholecystokinin / Q000819:agonists / Q000737:chemistry; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D019440:Anti-Obesity Agents; C511142:Ccl28 protein, mouse; D019742:Chemokines, CC; C488719:GI 181771X; D007211:Indoles; D008744:Methylamines; D010879:Piperazines; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; C118846:SR 146131; D013844:Thiazoles; D001569:Benzodiazepines; D000077489:Piperazine