Rational design of a novel peripherally-restricted, orally active CB(1) cannabinoid antagonist containing a 2,3-diarylpyrrole motif

Laurent Hortala; Murielle Rinaldi-Carmona; Christian Congy; Laurent Boulu; Freddy Sadoun; Gérard Fabre; Olivier Finance; Francis Barth

doi:10.1016/j.bmcl.2010.06.017

Rational design of a novel peripherally-restricted, orally active CB(1) cannabinoid antagonist containing a 2,3-diarylpyrrole motif

Bioorg Med Chem Lett. 2010 Aug 1;20(15):4573-7. doi: 10.1016/j.bmcl.2010.06.017. Epub 2010 Jun 8.

Authors

Laurent Hortala¹, Murielle Rinaldi-Carmona, Christian Congy, Laurent Boulu, Freddy Sadoun, Gérard Fabre, Olivier Finance, Francis Barth

Affiliation

¹ Exploratory Unit, Sanofi-aventis R&D, 371 rue du Professeur Joseph Blayac, Montpellier, France.

PMID: 20584609
DOI: 10.1016/j.bmcl.2010.06.017

Abstract

A new series of 2,3-diarylpyrroles have been prepared and evaluated as CB(1) antagonists. Modulation of the topological polar surface area allowed the identification of high affinity peripherally-restricted CB(1) antagonists. Compound 11, obtained after further optimization of the metabolic profile displayed very low brain penetration, yet was able to reverse CP55940-induced gastrointestinal transit inhibition following oral administration.

MeSH terms

Administration, Oral
Animals
Brain / metabolism
Drug Design
Gastrointestinal Transit / drug effects
Piperidines / chemical synthesis
Piperidines / chemistry*
Piperidines / pharmacology
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Pyrroles / chemical synthesis
Pyrroles / chemistry*
Pyrroles / pharmacology
Rats
Receptor, Cannabinoid, CB1 / antagonists & inhibitors
Receptor, Cannabinoid, CB1 / metabolism
Rimonabant

Substances

Piperidines
Pyrazoles
Pyrroles
Receptor, Cannabinoid, CB1
Rimonabant