title: Synthesis and evaluation of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-aminopropanamide as human cannabinoid-1 receptor (CB1R) inverse agonists.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. wuduchemistry@gmail.com
authors.forename: Wu
authors.initials: W
authors.lastname: Du
authors.forename: James P
authors.initials: JP
authors.lastname: Jewell
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Colandrea
authors.forename: Jing C
authors.initials: JC
authors.lastname: Xiao
authors.forename: Julie
authors.initials: J
authors.lastname: Lao
authors.forename: Chun-Pyn
authors.initials: CP
authors.lastname: Shen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bateman
authors.forename: Vijay B G
authors.initials: VB
authors.lastname: Reddy
authors.forename: Sookhee N
authors.initials: SN
authors.lastname: Ha
authors.forename: Shrenik K
authors.initials: SK
authors.lastname: Shah
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D054314:Drug Inverse Agonism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism
chemical_list: D000577:Amides; D019440:Anti-Obesity Agents; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011994:Recombinant Proteins; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide