Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia

  • ACS Med Chem Lett. 2016 Dec 16;8(2):233-238. doi: 10.1021/acsmedchemlett.6b00461.
Michael R Wood  1 ,  Meredith J Noetzel  1 ,  Bruce J Melancon  1 ,  Michael S Poslusney  2 ,  Kellie D Nance  2 ,  Miguel A Hurtado  2 ,  Vincent B Luscombe  1 ,  Rebecca L Weiner  1 ,  Alice L Rodriguez  1 ,  Atin Lamsal  1 ,  Sichen Chang  1 ,  Michael Bubser  1 ,  Anna L Blobaum  1 ,  Darren W Engers  1 ,  Colleen M Niswender  3 ,  Carrie K Jones  3 ,  Nicholas J Brandon  4 ,  Michael W Wood  4 ,  Mark E Duggan  4 ,  P Jeffrey Conn  3 ,  Thomas M Bridges  1 ,  Craig W Lindsley  1
Affiliations
  • 1. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
  • 3. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 4. AstraZeneca Neuroscience , Innovative Medicines Biotech Unit, 141 Portland Street, Cambridge, Massachusetts 02139, United States.
PMID: 28197318 DOI: 10.1021/acsmedchemlett.6b00461
Abstract

Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable Muscarinic Acetylcholine Receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.

Keywords
Positive allosteric modulator (PAM); VU0467485; muscarinic acetylcholine receptor 4 (M4); schizophrenia.
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