Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as α7 nicotinic acetylcholine receptor agonists

Abstract 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.