Bioisosteric replacement of the hydrazide pharmacophore of the cannabinoid-1 receptor antagonist SR141716A. Part I: potent, orally-active 1,4-disubstituted imidazoles

Robert L Dow; John R Hadcock; Dennis O Scott; Steven R Schneider; Ernest S Paight; Philip A Iredale; Philip A Carpino; David A Griffith; Marlys Hammond; Paul Dasilva-Jardine

doi:10.1016/j.bmcl.2009.07.130

Bioisosteric replacement of the hydrazide pharmacophore of the cannabinoid-1 receptor antagonist SR141716A. Part I: potent, orally-active 1,4-disubstituted imidazoles

Bioorg Med Chem Lett. 2009 Sep 15;19(18):5351-4. doi: 10.1016/j.bmcl.2009.07.130. Epub 2009 Aug 6.

Authors

Robert L Dow¹, John R Hadcock, Dennis O Scott, Steven R Schneider, Ernest S Paight, Philip A Iredale, Philip A Carpino, David A Griffith, Marlys Hammond, Paul Dasilva-Jardine

Affiliation

¹ Pfizer Global Research and Development, Groton, CT 06340, USA. robert.l.dow@pfizer.com

PMID: 19683918
DOI: 10.1016/j.bmcl.2009.07.130

Abstract

A new series of CB(1) receptor antagonists incorporating an imidazole-based isosteric replacement for the hydrazide moiety of rimonabant (SR141716) is disclosed. Members of this imidazole series possess potent/selective binding to the rCB(1) receptor and exhibit potent hCB(1) functional activity. Isopropyl analog 9a demonstrated activity in the tetrad assay and was orally-active in a food intake model.

MeSH terms

Animals
Humans
Imidazoles / chemistry*
Imidazoles / pharmacokinetics
Imidazoles / pharmacology*
Models, Molecular
Molecular Conformation
Piperidines / chemistry*
Piperidines / pharmacokinetics
Piperidines / pharmacology*
Pyrazoles / chemistry*
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology*
Rats
Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
Receptor, Cannabinoid, CB1 / metabolism*
Rimonabant
Structure-Activity Relationship

Substances

Imidazoles
Piperidines
Pyrazoles
Receptor, Cannabinoid, CB1
Rimonabant