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

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

Research square

Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Effects of the Muscarinic M 1 Positive Allosteric Modulator VU0467319 for Alzheimer’s disease: A Single Ascending-Dose Study in Healthy Participants

Article

作者: Gong, Xuewen ; Albert, Kimberly M. ; Bubser, Michael ; Blackford, Jennifer U. ; Lindsley, Craig W. ; Conn, P. Jeffrey ; Key, Alexandra P. ; Jones, Carrie K. ; Newhouse, Paul A. ; Rook, Jerri M. ; Conley, Alexander C. ; Russell, Jason K.

Abstract

The development of cholinergic neurotransmitter based cognitive enhancers for Alzheimer’s disease and other neuropsychiatric disorders have focused recently on allosteric modulation of specific muscarinic acetylcholine receptor (mAChR) subtypes to reduce dose-limiting side-effects that have been the hallmark of earlier orthosteric mAChR agonists. VU0467319 (VU319) is an investigational positive allosteric modulator of the M₁ mAChR. A Phase 1 first-in-human study was conducted assessing safety and brain activity utilizing cognitive tasks and event-related potentials (ERPs) in single-ascending dose and food effect studies. VU319 was given orally to 52 healthy volunteers aged 18–55 years. The single ascending dose study tested 40 participants in five dose escalating cohorts (60, 120, 240, 400, 600 mg; 6 VU319/2 placebo per dose). The food effect study involved 12 participants, 10 VU319 (120 mg)/2 placebo. Exploratory cognitive and electrophysiological tasks were examined pre-dosing and at 5 hours post-dose. Tolerability was good with no observed dose limiting side effects throughout the full dose range tested. Drug exposure increased with dose in a less than dose-proportional manner with a half-life ranging from 36 to 43 hours. Absorption was increased with food. Exploratory cognitive/ERP testing showed evidence for drug-induced CNS activity on higher doses of VU319 compared to placebo. Single dose VU319 across five ascending cohorts appeared to have a favorable safety profile and a PK profile consistent with once daily dosing. Target engagement results suggest stimulation of the cholinergic system functioning in healthy adults following a single dose of VU319. These results provide a strong foundation for further studies of positive allosteric modulators of muscarinic M₁ receptors for potential cognitive or behavioral benefits.

100 项与 VU-319 相关的药物交易

登录后查看更多信息