Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core

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Abstract

This Letter details the discovery and subsequent optimization of a novel M4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M4 PAM chemotypes. Optimized compounds in this series demonstrated improved M4 PAM potency on both human and rat M4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma Kp = 5.3, Kp,uu = 2.4; MDCK-MDR1 (P-gp) ER = 1.1).

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Acknowledgments

We thank the NIH U01MH087965 (Vanderbilt NCDDG). We also thank William K. Warren, Jr. and the William K. Warren Foundation who funded the William K. Warren, Jr. Chair in Medicine (to C.W.L.).

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