Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes.
A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.
Discovery and Preclinical Sciences, Merck Research Laboratories, Rahway, NJ 07065, USA. yusheng_xiong@merck.com
Yusheng
Y
Xiong
Jian
J
Guo
Mari R
MR
Candelore
Rui
R
Liang
Corey
C
Miller
Qing
Q
Dallas-Yang
Guoqiang
G
Jiang
Peggy E
PE
McCann
Sajjad A
SA
Qureshi
Xinchun
X
Tong
Shiyao Sherrie
SS
Xu
Jackie
J
Shang
Stella H
SH
Vincent
Laurie M
LM
Tota
Michael J
MJ
Wright
Xiaodong
X
Yang
Bei B
BB
Zhang
James R
JR
Tata
Emma R
ER
Parmee
D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004285:Dogs; D005934:Glucagon / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D020128:Inhibitory Concentration 50; D008253:Macaca mulatta; D051379:Mice; D008820:Mice, Obese; D008862:Microsomes, Liver / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000037:antagonists & inhibitors; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000037:antagonists & inhibitors; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000037:antagonists & inhibitors; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D009281:Naphthalenes
D001786:Blood Glucose; D005934:Glucagon; D000067757:Glucagon-Like Peptide-1 Receptor; D011720:Pyrazoles; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D015091:beta-Alanine; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; C031280:pyrazole; C575263:N-((4-(1-(3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl)ethyl)phenyl)carbonyl)-beta-alanine; D009281:Naphthalenes; C041086:gastric inhibitory polypeptide receptor