Discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity.
This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure-activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.
Yan
Lin
L
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. lin_yan@merck.com
Huo
Pei
P
Debenham
John S
JS
Madsen-Duggan
Christina B
CB
Lao
Julie
J
Chen
Richard Z
RZ
Xiao
Jing Chen
JC
Shen
Chun-Pyn
CP
Stribling
D Sloan
DS
Shearman
Lauren P
LP
Strack
Alison M
AM
Tsou
Nancy
N
Ball
Richard G
RG
Wang
Junying
J
Tong
Xinchun
X
Bateman
Thomas J
TJ
Reddy
Vijay B G
VB
Fong
Tung M
TM
Hale
Jeffrey J
JJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004285:Dogs; D054314:Drug Inverse Agonism; D004435:Eating / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D020719:Glucuronides / Q000378:metabolism; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008968:Molecular Conformation; D011714:Pyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019440:Anti-Obesity Agents; D051638:Ether-A-Go-Go Potassium Channels; D020719:Glucuronides; C550156:N-(6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano(2,3-b)pyridin-4-yl)-5-methyl-1H-pyrazole-3-carboxamide; D011714:Pyrans; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1