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

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