title: Diphenyl purine derivatives as peripherally selective cannabinoid receptor 1 antagonists.
abstract: Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS.
authors.affiliation: Discovery Sciences, Research Triangle Institute, 3040 Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Fulp
authors.forename: Katherine
authors.initials: K
authors.lastname: Bortoff
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Herbert
authors.initials: H
authors.lastname: Seltzman
authors.forename: James
authors.initials: J
authors.lastname: Mathews
authors.forename: Rodney
authors.initials: R
authors.lastname: Snyder
authors.forename: Tim
authors.initials: T
authors.lastname: Fennell
authors.forename: Rangan
authors.initials: R
authors.lastname: Maitra
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry*; D001921:Brain / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004285:Dogs; D015195:Drug Design; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001713:Biphenyl Compounds; D002118:Calcium; D063387:Cannabinoid Receptor Antagonists; D011687:Purines; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides; C577954:N-(1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)-4-phenylpiperidin-4-yl)methanesulfonamide; C010574:biphenyl