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

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.

SUBMITTER: Wood MR

PROVIDER: S-EPMC5304297 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Wood Michael R MR Noetzel Meredith J MJ Melancon Bruce J BJ Poslusney Michael S MS Nance Kellie D KD Hurtado Miguel A MA Luscombe Vincent B VB Weiner Rebecca L RL Rodriguez Alice L AL Lamsal Atin A Chang Sichen S Bubser Michael M Blobaum Anna L AL Engers Darren W DW Niswender Colleen M CM Jones Carrie K CK Brandon Nicholas J NJ Wood Michael W MW Duggan Mark E ME Conn P Jeffrey PJ Bridges Thomas M TM Lindsley Craig W CW

ACS medicinal chemistry letters 20161216 2

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 precl ...[more]

PMID: 28197318

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