Referenced in: none

Automatically associated channels: Kv11.1

Title: Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists.

Authors: Daniel P Walker, Donn G Wishka, David W Piotrowski, Shaojuan Jia, Steven C Reitz, Karen M Yates, Jason K Myers, Tatiana N Vetman, Brandon J Margolis, E Jon Jacobsen, Brad A Acker, Vincent E Groppi, Mark L Wolfe, Bruce A Thornburgh, Paula M Tinholt, Luz A Cortes-Burgos, Rodney R Walters, Matthew R Hester, Eric P Seest, Lester A Dolak, Fusen Han, Barbara A Olson, Laura Fitzgerald, Brian A Staton, Thomas J Raub, Mihaly Hajos, William E Hoffmann, Kai S Li, Nicole R Higdon, Theron M Wall, Raymond S Hurst, Erik H F Wong, Bruce N Rogers

Journal, date & volume: Bioorg. Med. Chem., 2006 Dec 15 , 14, 8219-48

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17011782

Abstract
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 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.