Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists.
Walker DP,
Wishka DG,
Piotrowski DW,
Jia S,
Reitz SC,
Yates KM,
Myers JK,
Vetman TN,
Margolis BJ,
Jacobsen EJ,
Acker BA,
Groppi VE,
Wolfe ML,
Thornburgh BA,
Tinholt PM,
Cortes-Burgos LA,
Walters RR,
Hester MR,
Seest EP,
Dolak LA,
Han F,
Olson BA,
Fitzgerald L,
Staton BA,
Raub TJ,
Hajos M,
Hoffmann WE,
Li KS,
Higdon NR,
Wall TM,
Hurst RS,
Wong EH,
Rogers BN.
Neuroscience Research, Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340, USA.
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.
PMID: 17011782 [PubMed - indexed for MEDLINE]