Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists.

Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA. ivar.mcdonald@bms.com

Bioorganic & medicinal chemistry letters 2013 Mar 15

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High throughput screening led to the identification of a novel series of quinolone α7 nicotinic acetylcholine receptor (nAChR) agonists. Optimization of an HTS hit (1) led to 4-phenyl-1-(quinuclidin-3-ylmethyl)quinolin-2(1H)-one, which was found to be potent and selective. Poor brain penetrance in this series was attributed to transporter-mediated efflux, which was in turn due to high pKa. A novel 4-fluoroquinuclidine significantly lowered the pKa of the quinuclidine moiety, reducing efflux as measured by a Caco-2 assay. Copyright © 2013 Elsevier Ltd. All rights reserved.

Citation

Ivar M McDonald, Robert A Mate, F Christopher Zusi, Hong Huang, Debra J Post-Munson, Meredith A Ferrante, Lizbeth Gallagher, Robert L Bertekap, Ronald J Knox, Barbara J Robertson, David G Harden, Daniel G Morgan, Nicholas J Lodge, Steven I Dworetzky, Richard E Olson, John E Macor. Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists. Bioorganic & medicinal chemistry letters. 2013 Mar 15;23(6):1684-8