Discovery of VU0467485/AZ13713945: An M4 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

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. eCollection 2017 Feb 9.

Authors

Michael R Wood¹, Meredith J Noetzel¹, Bruce J Melancon¹, Michael S Poslusney², Kellie D Nance², Miguel A Hurtado², Vincent B Luscombe¹, Rebecca L Weiner¹, Alice L Rodriguez¹, Atin Lamsal¹, Sichen Chang¹, Michael Bubser¹, Anna L Blobaum¹, Darren W Engers¹, Colleen M Niswender³, Carrie K Jones³, Nicholas J Brandon⁴, Michael W Wood⁴, Mark E Duggan⁴, P Jeffrey Conn³, Thomas M Bridges¹, Craig W Lindsley¹

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.

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.

Abstract

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