Discovery of a new class of ghrelin receptor antagonists.
A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca(2+) concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties.
Amgen Inc., 1120 Veterans Boulevard, ASF2-3, South San Francisco, CA 94080, USA. jmihalic@amgen.com
Jeffrey T
JT
Mihalic
Yong-Jae
YJ
Kim
Mike
M
Lizarzaburu
Xiaoqi
X
Chen
Jeff
J
Deignan
Malgorzata
M
Wanska
Ming
M
Yu
Jiasheng
J
Fu
Xi
X
Chen
Alex
A
Zhang
Richard
R
Connors
Lingming
L
Liang
Michelle
M
Lindstrom
Ji
J
Ma
Liang
L
Tang
Kang
K
Dai
Leping
L
Li
D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008163:Luminescent Measurements; D009765:Obesity / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D054440:Receptors, Ghrelin; D001569:Benzodiazepines; D002118:Calcium