Synthesis and cannabinoid-1 receptor binding affinity of conformationally constrained analogs of taranabant

Ihor E Kopka; Linus S Lin; James P Jewell; Thomas J Lanza; Tung M Fong; Chun-Pyn Shen; Zhege J Lao; Sookhee Ha; Laurie G Castonguay; Lex Van der Ploeg; Mark T Goulet; William K Hagmann

doi:10.1016/j.bmcl.2010.06.127

Synthesis and cannabinoid-1 receptor binding affinity of conformationally constrained analogs of taranabant

Bioorg Med Chem Lett. 2010 Aug 15;20(16):4757-61. doi: 10.1016/j.bmcl.2010.06.127. Epub 2010 Jul 1.

Authors

Ihor E Kopka¹, Linus S Lin, James P Jewell, Thomas J Lanza, Tung M Fong, Chun-Pyn Shen, Zhege J Lao, Sookhee Ha, Laurie G Castonguay, Lex Van der Ploeg, Mark T Goulet, William K Hagmann

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.

PMID: 20643546
DOI: 10.1016/j.bmcl.2010.06.127

Abstract

The design, synthesis, and binding activity of ring constrained analogs of the acyclic cannabinoid-1 receptor (CB1R) inverse agonist taranabant 1 are described. The initial inspiration for these taranabant derivatives was its conformation 1a, determined by (1)H NMR, X-ray, and molecular modeling. The constrained analogs were all much less potent than their acyclic parent structure. The results obtained are discussed in the context of a predicted binding of 1 to a homology model of CB1R.

MeSH terms

Amides / chemical synthesis
Amides / chemistry*
Amides / pharmacology
Anti-Obesity Agents / chemical synthesis*
Anti-Obesity Agents / chemistry
Anti-Obesity Agents / pharmacology
Computer Simulation
Humans
Models, Molecular
Molecular Conformation
Protein Binding
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology
Receptor, Cannabinoid, CB1 / chemistry*
Receptor, Cannabinoid, CB1 / metabolism

Substances

Amides
Anti-Obesity Agents
Pyridines
Receptor, Cannabinoid, CB1
N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide