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

• Published in: Journal of medicinal chemistry 2005-03, Vol.48 (6), p.1823-1838
• Main Authors: Lange, Jos H. M, van Stuivenberg, Herman H, Coolen, Hein K. A. C, Adolfs, Tiny J. P, McCreary, Andrew C, Keizer, Hiskias G, Wals, Henri C, Veerman, Willem, Borst, Alice J. M, de Looff, Wouter, Verveer, Peter C, Kruse, Chris G
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; CHO Cells; Cricetinae; Cricetulus; Cyclohexanols - antagonists & inhibitors; Hypotension - chemically induced; Hypothermia - chemically induced; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Medical sciences; Mice; Miscellaneous; Models, Molecular; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; 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; Stereoisomerism; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040843r

Series of thiazoles, triazoles, and imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB1 receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB1 and hCB2) receptor assays. The thiazoles, triazoles, and imidazoles elicited in vitroCB1 antagonistic activities and in general exhibited considerable CB1 vs CB2 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.