Synthesis, SAR and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles as potent cannabinoid CB(1) receptor antagonists

Jos H M Lange; Martina A W van der Neut; Arnold P den Hartog; Henri C Wals; Jan Hoogendoorn; Herman H van Stuivenberg; Bernard J van Vliet; Chris G Kruse

doi:10.1016/j.bmcl.2010.01.049

Synthesis, SAR and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles as potent cannabinoid CB(1) receptor antagonists

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1752-7. doi: 10.1016/j.bmcl.2010.01.049. Epub 2010 Jan 20.

Authors

Jos H M Lange¹, Martina A W van der Neut, Arnold P den Hartog, Henri C Wals, Jan Hoogendoorn, Herman H van Stuivenberg, Bernard J van Vliet, Chris G Kruse

Affiliation

¹ Solvay Pharmaceuticals, Research Laboratories, Chemical Design & Synthesis Unit, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. jos.lange@solvay.com

PMID: 20137935
DOI: 10.1016/j.bmcl.2010.01.049

Abstract

The synthesis, structure-activity relationship (SAR) studies and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles are described. The target compounds 6-18 represent a novel class of potent and selective CB(1) receptor antagonists. Based on X-ray diffraction data, the orally active 17 is shown to elicit a different intramolecular H-bonding mode as compared to ibipinabant (3) and SLV330 (4).

MeSH terms

Administration, Oral
Animals
Anti-Obesity Agents / chemical synthesis*
Anti-Obesity Agents / chemistry
Anti-Obesity Agents / pharmacology
Binding Sites
Crystallography, X-Ray
Humans
Hydrogen Bonding
Molecular Conformation
Pyrazoles / chemical synthesis*
Pyrazoles / chemistry
Pyrazoles / pharmacology
Rats
Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
Receptor, Cannabinoid, CB1 / metabolism
Structure-Activity Relationship
Sulfonamides / chemical synthesis*
Sulfonamides / chemistry
Sulfonamides / pharmacology

Substances

Anti-Obesity Agents
Pyrazoles
Receptor, Cannabinoid, CB1
Sulfonamides