2. Academic Validation
  3. VU6007477, a Novel M1 PAM Based on a Pyrrolo[2,3- b]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events

VU6007477, a Novel M1 PAM Based on a Pyrrolo[2,3- b]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events

  • ACS Med Chem Lett. 2018 Sep 4;9(9):917-922. doi: 10.1021/acsmedchemlett.8b00261.
Julie L Engers 1,  Elizabeth S Childress 1,  Madeline F Long 1,  Rory A Capstick 1,  Vincent B Luscombe 1,  Hekyung P Cho 1,  Jonathan W Dickerson 1,  Jerri M Rook 1,  Anna L Blobaum 1,  Colleen M Niswender 1,  Darren W Engers 1,  P Jeffrey Conn 1,  Craig W Lindsley 1
Affiliations

Affiliation

  • 1 Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Department of Chemistry, Department of Biochemistry, and Vanderbilt Kennedy Center, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 30258541 DOI: 10.1021/acsmedchemlett.8b00261
Abstract

Herein, we report the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel pyrrolo[2,3-b]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 M1 PAM potency (EC50 = 230 nM, 93% ACh max), minimal M1 agonist activity (agonist EC50 > 10 μM), good CNS penetration (rat brain/plasma K p = 0.28, K p,uu = 0.32; mouse K p = 0.16, K p,uu = 0.18), and no cholinergic adverse events (AEs, e.g., seizures). This work demonstrates that within a chemical series prone to robust M1 ago-PAM activity, SAR can result, which affords pure M1 PAMs, devoid of cholinergic toxicity/seizure liability.

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