Discovery of a novel, CNS penetrant M PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core.

Bewley BR, Spearing PK, Weiner RL, Luscombe VB, Zhan X, Chang S, Cho HP, Rodriguez AL, Niswender CM, Conn PJ, Bridges TM, Engers DW, Lindsley CW
Bioorg Med Chem Lett. 2017 27 (18): 4274-4279

PMID: 28866269 · PMCID: PMC5688877 · DOI:10.1016/j.bmcl.2017.08.043

This Letter details the discovery and subsequent optimization of a novel M PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M PAM chemotypes. Optimized compounds in this series demonstrated improved M PAM potency on both human and rat M (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma K=5.3, K=2.4; MDCK-MDR1 (P-gp) ER=1.1).

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MeSH Terms (11)

Animals Central Nervous System Dose-Response Relationship, Drug Drug Discovery Humans Molecular Structure Piperidines Quinolines Rats Receptor, Muscarinic M4 Structure-Activity Relationship

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