ABSTRACT
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.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Pyrans/chemical synthesis , Pyridines/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Binding, Competitive , Body Weight/drug effects , Cell Line , Cricetinae , Cricetulus , Crystallography, X-Ray , Dogs , Drug Inverse Agonism , Eating/drug effects , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Glucuronides/metabolism , Haplorhini , Hepatocytes/metabolism , Humans , Mice , Mice, Knockout , Models, Molecular , Molecular Conformation , Pyrans/pharmacokinetics , Pyrans/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Receptor, Cannabinoid, CB1/genetics , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Obesity is a chronic medical condition that is affecting large population throughout the world. CB1 as a target for treatment of obesity has been under intensive studies. Taranabant was discovered and then developed by Merck as the 1st generation CB1R inverse agonist. Reported here is part of our effort on the 2nd generation of CB1R inverse agonist from the acyclic amide scaffold. We replaced the oxygen linker in taranabant with nitrogen and prepared a series of amino heterocyclic analogs through a divergent synthesis. Although in general, the amine linker gave reduced binding affinity, potent and selective CB1R inverse agonist was identified from the amino heterocycle series. Molecular modeling was applied to study the binding of the amino heterocycle series at CB1 binding site. The in vitro metabolism of representative members was studied and only trace glucuronidation was found. Thus, it suggests that the right hand side of the molecule may not be the appropriate site for glucuronidation.
Subject(s)
Amides/chemistry , Anti-Obesity Agents/chemistry , Pyridines/chemistry , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Binding Sites , Computer Simulation , Drug Inverse Agonism , Humans , Microsomes, Liver/metabolism , Pyridines/pharmacology , Rats , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/metabolism , Recombinant Proteins/agonists , Recombinant Proteins/metabolismABSTRACT
High-throughput screening revealed diaryl pyrazole 3 as a selective albeit modest cholecystokinin 1 receptor (CCK1R) agonist. SAR studies led to the discovery and optimization of a novel class of 1,2-diaryl imidazole carboxamides. Compound 44, which was profiled extensively, showed good in vivo mouse gallbladder emptying (mGBE) and lean mouse overnight food intake (ONFI) reduction activities.
