Bioisosteric replacements of the pyrazole moiety of rimonabant: synthesis, biological properties, and molecular modeling investigations of thiazoles, triazoles, and imidazoles as potent and selective CB1 cannabinoid receptor antagonists

Jos H M Lange; Herman H van Stuivenberg; Hein K A C Coolen; Tiny J P Adolfs; Andrew C McCreary; Hiskias G Keizer; Henri C Wals; Willem Veerman; Alice J M Borst; Wouter de Looff; Peter C Verveer; Chris G Kruse

doi:10.1021/jm040843r

Bioisosteric replacements of the pyrazole moiety of rimonabant: synthesis, biological properties, and molecular modeling investigations of thiazoles, triazoles, and imidazoles as potent and selective CB1 cannabinoid receptor antagonists

J Med Chem. 2005 Mar 24;48(6):1823-38. doi: 10.1021/jm040843r.

Authors

Jos H M Lange¹, Herman H van Stuivenberg, Hein K A C Coolen, Tiny J P Adolfs, Andrew C McCreary, Hiskias G Keizer, Henri C Wals, Willem Veerman, Alice J M Borst, Wouter de Looff, Peter C Verveer, Chris G Kruse

Affiliation

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

PMID: 15771428
DOI: 10.1021/jm040843r

Abstract

Series of thiazoles, triazoles, and imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB(1) receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The thiazoles, triazoles, and imidazoles elicited in vitro( )()CB(1) antagonistic activities and in general exhibited considerable CB(1) vs CB(2) receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure-activity relationship (SAR) study revealed a close correlation between the biological results in the imidazole and pyrazole series.

MeSH terms

Administration, Oral
Animals
CHO Cells
Cricetinae
Cricetulus
Cyclohexanols / antagonists & inhibitors
Hypotension / chemically induced
Hypothermia / chemically induced
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacology
Mice
Models, Molecular
Molecular Conformation
Piperidines / chemical synthesis*
Piperidines / chemistry*
Piperidines / pharmacology
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Radioligand Assay
Rats
Receptor, Cannabinoid, CB1 / agonists
Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
Receptor, Cannabinoid, CB2 / drug effects
Rimonabant
Stereoisomerism
Structure-Activity Relationship
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology
Triazoles / chemical synthesis*
Triazoles / chemistry
Triazoles / pharmacology

Substances

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide
Cyclohexanols
Imidazoles
Piperidines
Pyrazoles
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Thiazoles
Triazoles
3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
Rimonabant