Identification of piperazine-bisamide GHSR antagonists for the treatment of obesity.
Piperazine-bisamide analogs were discovered as partial agonists of human growth hormone secretagogue receptor (GHSR) in a high throughput screen. The partial agonists were optimized for potency and converted into antagonists through structure-activity relationship (SAR) studies. The efforts also led to the identification of potent antagonist with favorable PK profile suitable as a tool compound for in vivo studies.
Yu
Ming
M
Amgen Inc. 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. yum@amgen.com
Lizarzaburu
Mike
M
Beckmann
Holger
H
Connors
Richard
R
Dai
Kang
K
Haller
Katrin
K
Li
Cong
C
Liang
Lingming
L
Lindstrom
Michelle
M
Ma
Ji
J
Motani
Alykhan
A
Wanska
Malgorzata
M
Zhang
Alex
A
Li
Leping
L
Medina
Julio C
JC
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D019440:Anti-Obesity Agents; D007211:Indoles; D010879:Piperazines; D054440:Receptors, Ghrelin