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Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators |
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| Authors: | Albrecht Brian K Berry Virginia Boezio Alessandro A Cao Lei Clarkin Kristie Guo Wenhong Harmange Jean-Christophe Hierl Markus Huang Liyue Janosky Brett Knop Johannes Malmberg Annika McDermott Jeff S Nguyen Hung Q Springer Stephanie K Waldon Daniel Woodin Katrina McDonough Stefan I |
| Affiliation: | Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA, USA. brian.albrecht@constellationpharma.com |
| Abstract: | The discovery of a series of small molecule alpha4beta2 nAChR potentiators is reported. The structure-activity relationship leads to potent compounds selective against nAChRs including alpha3beta2 and alpha3beta4 and optimized for CNS penetrance. Compounds increased currents through recombinant alpha4beta2 nAChRs, yet did not compete for binding with the orthosteric ligand cytisine. High potency and efficacy on the rat channel combined with good PK properties will allow testing of the alpha4beta2 potentiator mechanism in animal models of disease. |
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