Poslunsey Michael S, Wood Michael R, Han Changho, Stauffer Shaun R, Panarese Joseph D, Melancon Bruce J, Engers Julie L, Dickerson Jonathan W, Peng Weimin, Noetzel Meredith J, Cho Hyekyung P, Rodriguez Alice L, Hopkins Corey R, Morrison Ryan, Crouch Rachel D, Bridges Thomas M, Blobaum Anna L, Boutaud Olivier, Daniels J Scott, Kates Michael J, Castelhano Arlindo, Rook Jerri M, Niswender Colleen M, Jones Carrie K, Conn P Jeffrey, Lindsley Craig W
Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
ACS Chem Neurosci. 2025 Jan 1;16(1):95-107. doi: 10.1021/acschemneuro.4c00769. Epub 2024 Dec 11.
Herein we detail the of VU0467319 (VU319), an M Positive Allosteric Modulator (PAM) clinical candidate that successfully completed a Phase I Single Ascending Dose (SAD) clinical trial. VU319 () is a moderately potent M PAM (M PAM EC = 492 nM ± 2.9 nM, 71.3 ± 9.9% ACh Max), with minimal M agonism (EC > 30 μM), that displayed high CNS penetration ( > 0.67 and > 0.9) and multispecies pharmacokinetics permissive of further development. Based on robust efficacy in multiple preclinical models of cognition, an ancillary pharmacology profile devoid of appreciable off-target activities, and a lack of cholinergic adverse effects (AEs) in rats, dogs and nonhuman primates, VU319 advanced into IND-enabling studies. After completing 4-week rat and dog GLP toxicology without AEs, including absence of cholinergic effects, the first in human Phase I SAD clinical trial of VU319 (NCT03220295) was performed at Vanderbilt, where a similar lack of adverse effects, including absence of cholinergic effects was noted. Moreover, signals of target engagement were seen at the highest dose tested. Thus, VU319 demonstrated the feasibility of achieving selective targeting of central M muscarinic receptors without eliciting cholinergic AEs that have plagued other drugs targeting CNS cholinergic neurotransmission.
在此，我们详细介绍VU0467319（VU319），一种M阳性变构调节剂（PAM）临床候选药物，它成功完成了I期单剂量递增（SAD）临床试验。VU319（）是一种中等效力的M PAM（M PAM EC = 492 nM ± 2.9 nM，71.3 ± 9.9% ACh Max），具有最小的M激动作用（EC > 30 μM），显示出高中枢神经系统渗透性（> 0.67和> 0.9）以及多物种药代动力学，允许进一步开发。基于在多种认知临床前模型中的强大疗效、缺乏明显脱靶活性的辅助药理学特征以及在大鼠、狗和非人灵长类动物中缺乏胆碱能不良反应（AE），VU319进入了IND启用研究。在完成4周无AE的大鼠和狗GLP毒理学研究，包括无胆碱能效应后，VU319的首次人体I期SAD临床试验（NCT03220295）在范德比尔特进行，在那里也观察到类似的缺乏不良反应，包括无胆碱能效应。此外，在测试的最高剂量下观察到了靶点参与信号。因此，VU319证明了实现中枢M毒蕈碱受体选择性靶向而不引发困扰其他靶向中枢胆碱能神经传递药物的胆碱能AE的可行性。
