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

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• 作者：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
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：8
• 期：2
• 页码：233-238
• 全文大小：453K
• ISSN：1948-5875

文摘

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.