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
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 Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
ACS Med Chem Lett. 2016 Dec 16;8(2):233-238. doi: 10.1021/acsmedchemlett.6b00461. eCollection 2017 Feb 9.
Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M) positive allosteric modulators (PAMs). Compound (VU0467485) possesses robust M PAM potency across species and efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, (VU0467485) was evaluated as a preclinical development candidate.
在此，我们报告了一系列强效、选择性且口服生物可利用的毒蕈碱型乙酰胆碱受体4（M4）正向变构调节剂（PAMs）的构效关系。化合物（VU0467485）在各物种中均具有强大的M4 PAM活性，且在精神分裂症临床前模型中有效。结合吸引人的药物代谢动力学（DMPK）特征和合适的预测人体药代动力学（PK），（VU0467485）被评估为临床前开发候选药物。
