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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 18; pp. 5351 - 5354
• Main Authors: Dow, Robert L., Hadcock, John R., Scott, Dennis O., Schneider, Steven R., Paight, Ernest S., Iredale, Philip A., Carpino, Philip A., Griffith, David A., Hammond, Marlys, DaSilva-Jardine, Paul
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.09.2009; Elsevier
• Subjects: Animals; Biological and medical sciences; Cannabinoid-1 receptor antagonist; Food intake inhibition; General and cellular metabolism. Vitamins; Humans; Imidazole isostere; Imidazoles - chemistry; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperidines - chemistry; Piperidines - pharmacokinetics; Piperidines - pharmacology; Pyrazoles - chemistry; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Rats; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - metabolism; SR-141716; Structure-Activity Relationship; Food intake inhibition; Cannabinoid-1 receptor antagonist; Imidazole isostere; SR-141716; CB1 cannabinoid receptor; Imidazole derivatives; Rat; Rodentia; Oral administration; Bioavailability; In vitro; Modeling; Biological activity; In vivo; Vertebrata; Mammalia; Rimonabant; Animal; Chlorine Organic compounds; Pyrazole derivatives; Anorectic; Antagonist; Pharmacokinetics; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.07.130

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.