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

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

来源：ACS Medicinal Chemistry Letters, 2017, 8(2): 233-238.

DOI：10.1021/acsmedchemlett.6b00461

• Positive allosteric modulator (PAM)
• muscarinic acetylcholine receptor 4 (M-4)
• VU0467485
• schizophrenia

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.

• 出版日期2017-2