Discovery of VU0467485/AZ13713945: An M-4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia

Michael R. Wood; Meredith J. Noetzel; Bruce J. Melancon; Michael S. Poslusney; Kellie D. Nance; Miguel A. Hurtado; Vincent B. Luscombe; Rebecca L. Weiner; Alice L. Rodriguez; Atin Lamsal; Sichen Chang; Michael Bubser; Anna L. Blobaum; Darren W. Engers; Colleen M. Niswender; Carrie K. Jones; Nicholas J. Brandon; Michael W. Wood; Mark E. Duggan; P. Jeffrey Conn; Thomas M. Bridges; Craig W. Lindsley

doi:10.1021/acsmedchemlett.6b00461

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Discovery of VU0467485/AZ13713945: An M-4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia

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Discovery of VU0467485/AZ13713945: An M-4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia

Michael R. Wood, Meredith J. Noetzel, Bruce J. Melancon, Michael S. Poslusney, Kellie D. Nance, Miguel A. Hurtado, Vincent B. Luscombe, Rebecca L. Weiner, Alice L. Rodriguez, Atin Lamsal, …

ACS medicinal chemistry letters, Vol.8(2), pp.233-238

02/01/2017

DOI: 10.1021/acsmedchemlett.6b00461

PMCID: PMC5304297

PMID: 28197318

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Abstract

Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M-4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M-4 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.

Chemistry, Medicinal

Life Sciences & Biomedicine

Pharmacology & Pharmacy

Science & Technology

Details

Title: Subtitle: Discovery of VU0467485/AZ13713945: An M-4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia
Creators: Michael R. Wood - Vanderbilt University
Meredith J. Noetzel - Vanderbilt University
Bruce J. Melancon - Vanderbilt University
Michael S. Poslusney - Vanderbilt University
Kellie D. Nance - Vanderbilt University
Miguel A. Hurtado - Vanderbilt University
Vincent B. Luscombe - Vanderbilt University
Rebecca L. Weiner - Vanderbilt University
Alice L. Rodriguez - Vanderbilt University
Atin Lamsal - Vanderbilt University
Sichen Chang - Vanderbilt University
Michael Bubser - Vanderbilt University
Anna L. Blobaum - Vanderbilt University
Darren W. Engers - Vanderbilt University
Colleen M. Niswender - Vanderbilt University
Carrie K. Jones - Vanderbilt University
Nicholas J. Brandon - AstraZeneca
Michael W. Wood - AstraZeneca
Mark E. Duggan - AstraZeneca
P. Jeffrey Conn - Vanderbilt University
Thomas M. Bridges - Vanderbilt University
Craig W. Lindsley - Vanderbilt University
Resource Type: Journal article
Publication Details: ACS medicinal chemistry letters, Vol.8(2), pp.233-238
Publisher: Amer Chemical Soc
DOI: 10.1021/acsmedchemlett.6b00461
PMID: 28197318
PMCID: PMC5304297
ISSN: 1948-5875
eISSN: 1948-5875
Number of pages: 6
Grant note: U01MH087965 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) William K. Warren Foundation U54HD083211 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Language: English
Date published: 02/01/2017
Academic Unit: Pulmonary Medicine; Stead Family Department of Pediatrics
Record Identifier: 9984353835202771

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