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Niswender Laboratory

VU6007477, a Novel M PAM Based on a Pyrrolo[2,3-]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events

AUTHORS

Engers JLJulie L , Childress ESElizabeth S , Long MFMadeline F , Capstick RARory A , Luscombe VBVincent B , Cho HPHekyung P , Dickerson JWJonathan W , Rook JMJerri M , Blobaum ALAnna L , Niswender CMColleen M , Engers DWDarren W , Conn PJP Jeffrey , Lindsley CWCraig W . ACS medicinal chemistry letters. 2018 9 4; 9(9). 917-922

ABSTRACT

Herein, we report the chemical optimization of a new series of M positive allosteric modulators (PAMs) based on a novel pyrrolo[2,3-]pyridine core, developed via scaffold hopping and iterative parallel synthesis. The vast majority of analogs in this series proved to display robust cholinergic seizure activity. However, by removal of the secondary hydroxyl group, VU6007477 resulted with good rat M PAM potency (EC = 230 nM, 93% ACh max), minimal M agonist activity (agonist EC > 10 μM), good CNS penetration (rat brain/plasma = 0.28, = 0.32; mouse = 0.16, = 0.18), and no cholinergic adverse events (AEs, e.g., seizures). This work demonstrates that within a chemical series prone to robust M ago-PAM activity, SAR can result, which affords pure M PAMs, devoid of cholinergic toxicity/seizure liability.

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