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.
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.
Du
Wu
W
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. wuduchemistry@gmail.com
Jewell
James P
JP
Lin
Linus S
LS
Colandrea
Vincent J
VJ
Xiao
Jing C
JC
Lao
Julie
J
Shen
Chun-Pyn
CP
Bateman
Thomas J
TJ
Reddy
Vijay B G
VB
Ha
Sookhee N
SN
Shah
Shrenik K
SK
Fong
Tung M
TM
Hale
Jeffrey J
JJ
Hagmann
William K
WK
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
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