VU-319(VU-319) - 药物靶点：M1 receptor_在研适应症：阿尔茨海默症_专利_临床

概要

基本信息

药物类型

小分子化药

别名-

靶点

M1 receptor

作用方式

调节剂

作用机制

M1 receptor调节剂(毒蕈碱型乙酰胆碱受体M1调节剂)

治疗领域

神经系统疾病

在研适应症

阿尔茨海默症

非在研适应症

认知功能障碍

原研机构

Vanderbilt University Medical Center

在研机构

Vanderbilt University Medical Center

非在研机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

2

项与 VU-319 相关的临床试验

NCT04051801

/ Withdrawn临床1期IIT

Multiple Ascending Dose Phase I Study of the M1 Positive Allosteric Modulator VU0467319

This is a safety study of the molecule VU319 to ascertain pharmacokinetic and pharmacodynamic data and test cognitive enhancement in healthy volunteers.

开始日期2021-05-25

申办/合作机构

Vanderbilt University Medical Center

NCT03220295

/ Completed临床1期IIT

Study of the M1 Positive Allosteric Modulator VU0467319

This is a safety study of the molecule VU319 to ascertain pharmacokinetic and pharmacodynamic data and test cognitive enhancement in healthy volunteers.

开始日期2017-07-28

申办/合作机构

Vanderbilt University

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100 项与 VU-319 相关的临床结果

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100 项与 VU-319 相关的转化医学

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100 项与 VU-319 相关的专利（医药）

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2

项与 VU-319 相关的文献（医药）

2025-01-01·ACS Chemical Neuroscience

Discovery of VU0467319: an M₁ Positive Allosteric Modulator Candidate That Advanced into Clinical Trials

Article

作者: Poslunsey, Michael S. ; Niswender, Colleen M. ; Han, Changho ; Rodriguez, Alice L. ; Melancon, Bruce J. ; Blobaum, Anna L. ; Engers, Julie L. ; Rook, Jerri M. ; Bridges, Thomas M. ; Castelhano, Arlindo ; Jones, Carrie K. ; Boutaud, Olivier ; Kates, Michael J. ; Lindsley, Craig W. ; Dickerson, Jonathan W. ; Panarese, Joseph D. ; Daniels, J. Scott ; Hopkins, Corey R. ; Wood, Michael R. ; Crouch, Rachel D. ; Noetzel, Meredith J. ; Morrison, Ryan ; Conn, P. Jeffrey ; Peng, Weimin ; Stauffer, Shaun R. ; Cho, Hyekyung P.

Herein we detail the first disclosure of VU0467319 (VU319), an M₁ Positive Allosteric Modulator (PAM) clinical candidate that successfully completed a Phase I Single Ascending Dose (SAD) clinical trial. VU319 (16) is a moderately potent M₁ PAM (M₁ PAM EC₅₀ = 492 nM ± 2.9 nM, 71.3 ± 9.9% ACh Max), with minimal M₁ agonism (EC₅₀ > 30 μM), that displayed high CNS penetration (K_ps > 0.67 and K_p,uus > 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 M₁ muscarinic receptors without eliciting cholinergic AEs that have plagued other drugs targeting CNS cholinergic neurotransmission.

2024-09-18·ACS Chemical Neuroscience

Discovery of VU6007496: Challenges in the Development of an M₁ Positive Allosteric Modulator Backup Candidate

Article

作者: Bollinger, Katrina A. ; Bender, Aaron M. ; Peng, Weimin ; Moran, Sean P. ; Rodriguez, Alice L. ; Capstick, Rory A. ; Presley, Christopher C. ; Blobaum, Anna L. ; Rook, Jerri M. ; Engers, Darren W. ; Niswender, Colleen M. ; Boutaud, Olivier ; Cho, Hyekyung P. ; Conn, P. Jeffrey ; Lindsley, Craig W. ; Dickerson, Jonathan W. ; Xiang, Zixiu ; Long, Madeline F. ; Engers, Julie L.

Herein we report progress toward a backup clinical candidate to the M₁ positive allosteric modulator (PAM) VU319/ACP-319. Scaffold-hopping from the pyrrolo[2,3-b]pyridine-based M₁ PAM VU6007477 to isomeric pyrrolo[3,2-b]pyridine and thieno[3,2-b]pyridine congeners identified several backup contenders. Ultimately, VU6007496, a pyrrolo[3,2-b]pyridine, advanced into late stage profiling, only to be plagued with unanticipated, species-specific metabolism and active/toxic metabolites which were identified in our phenotypic seizure liability in vivo screen, preventing further development. However, VU6007496 proved to be a highly selective and CNS penetrant M₁ PAM, with minimal agonism, that displayed excellent multispecies IV/PO pharmacokinetics (PK), CNS penetration, no induction of long-term depression (or cholinergic toxicity) and robust efficacy in novel object recognition (minimum effective dose = 3 mg/kg p.o.). Thus, VU6007496 can serve as another valuable in vivo tool compound in rats and nonhuman primates, but not mouse, to study selective M₁ activation.

100 项与 VU-319 相关的药物交易

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