Discovery and Optimization of Potent and CNS Penetrant M 5 -Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold

Discovery and Optimization of Potent and CNS Penetrant M 5 -Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold

The pharmacology of the M muscarinic acetylcholine receptor (mAChR) is the least understood of the five mAChR subtypes due to a historic lack of selective small molecule tools. To address this shortcoming, we have continued the optimization effort around the prototypical M positive allosteric modula...

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Veröffentlicht in:ACS chemical neuroscience 2018-07, Vol.9 (7), p.1572-1581
Hauptverfasser: Bender, Aaron M, Cho, Hyekyung P, Nance, Kellie D, Lingenfelter, Kaelyn S, Luscombe, Vincent B, Gentry, Patrick R, Voigtritter, Karl, Berizzi, Alice E, Sexton, Patrick M, Langmead, Christopher J, Christopoulos, Arthur, Locuson, Charles W, Bridges, Thomas M, Chang, Sichen, O'Neill, Jordan C, Zhan, Xiaoyan, Niswender, Colleen M, Jones, Carrie K, Conn, P Jeffrey, Lindsley, Craig W
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Sprache:eng
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Zusammenfassung:The pharmacology of the M muscarinic acetylcholine receptor (mAChR) is the least understood of the five mAChR subtypes due to a historic lack of selective small molecule tools. To address this shortcoming, we have continued the optimization effort around the prototypical M positive allosteric modulator (PAM) ML380 and have discovered and optimized a new series of M PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M PAM EC values
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.8b00126