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

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. Isopr...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-09, Vol.19 (18), p.5351-5354
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.07.130