title: Peripherally selective diphenyl purine antagonist of the CB1 receptor.
abstract: Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to date, the only clinically approved CB1 receptor antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant's withdrawal, several groups are pursuing peripherally selective CB1 antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl purine CB1 antagonist otenabant 1. Compound 9 (N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}pentanamide) is a potent, orally absorbed antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate the central effects of Δ(9)-tetrahydrocannabinol through the CB1 receptor.
authors.affiliation: Discovery Sciences, Research Triangle Institute , 3040 Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
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: Rodney
authors.initials: R
authors.lastname: Snyder
authors.forename: Tim
authors.initials: T
authors.lastname: Fennell
authors.forename: Julie A
authors.initials: JA
authors.lastname: Marusich
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
authors.forename: Herbert
authors.initials: H
authors.lastname: Seltzman
authors.forename: Rangan
authors.initials: R
authors.lastname: Maitra
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011687:Purines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D010880:Piperidines; D011687:Purines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C586843:N-(1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)piperidin-4-yl)pentanamide; C010574:biphenyl; C030985:purine
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