title: Design and synthesis of cannabinoid receptor 1 antagonists for peripheral selectivity.
abstract: Antagonists of cannabinoid receptor 1 (CB1) have potential for the treatment of several diseases such as obesity, liver disease, and diabetes. Recently, development of several CB1 antagonists was halted because of adverse central nervous system (CNS) related side effects observed with rimonabant, the first clinically approved CB1 inverse agonist. However, recent studies indicate that regulation of peripherally expressed CB1 with CNS-sparing compounds is a viable strategy to treat several important disorders. Our efforts aimed at rationally designing peripherally restricted CB1 antagonists have resulted in compounds that have limited blood-brain barrier (BBB) permeability and CNS exposure in preclinical in vitro and in vivo models. Typically, compounds with high topological polar surface areas (TPSAs) do not cross the BBB passively. Compounds with TPSAs higher than that for rimonabant (rimonabant TPSA = 50) and excellent functional activity with limited CNS penetration were identified. These compounds will serve as templates for further optimization.
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: Herbert
authors.initials: H
authors.lastname: Seltzman
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
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: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability; D004285:Dogs; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D008024:Ligands; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014508:Urea; D002118:Calcium