478169-77-6Relevant articles and documents
Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as α7 nicotinic acetylcholine receptor agonists
Walker, Daniel P.,Wishka, Donn G.,Piotrowski, David W.,Jia, Shaojuan,Reitz, Steven C.,Yates, Karen M.,Myers, Jason K.,Vetman, Tatiana N.,Margolis, Brandon J.,Jacobsen, E. Jon,Acker, Brad A.,Groppi, Vincent E.,Wolfe, Mark L.,Thornburgh, Bruce A.,Tinholt, Paula M.,Cortes-Burgos, Luz A.,Walters, Rodney R.,Hester, Matthew R.,Seest, Eric P.,Dolak, Lester A.,Han, Fusen,Olson, Barbara A.,Fitzgerald, Laura,Staton, Brian A.,Raub, Thomas J.,Hajos, Mihaly,Hoffmann, William E.,Li, Kai S.,Higdon, Nicole R.,Wall, Theron M.,Hurst, Raymond S.,Wong, Erik H.F.,Rogers, Bruce N.
, p. 8219 - 8248 (2007/10/03)
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the α7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed α7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
