Discovery of VU0467319: an M 1 Positive Allosteric Modulator Candidate That Advanced into Clinical Trials.

Autor:	Poslunsey MS; 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., Wood MR; 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., Han C; 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., Stauffer SR; 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., Panarese JD; 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., Melancon BJ; 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., Engers JL; 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., Dickerson JW; 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., Peng 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., Noetzel MJ; 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., Cho HP; 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., Rodriguez AL; 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., Hopkins CR; 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., Morrison R; 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., Crouch RD; 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., Bridges TM; 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., Blobaum AL; 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., Boutaud O; 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., Daniels JS; 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., Kates MJ; Davos Pharma, Upper Saddle River, New Jersey 07458, United States., Castelhano A; Davos Pharma, Upper Saddle River, New Jersey 07458, United States., Rook JM; 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., Niswender CM; 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.; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.; Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37232, United States.; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States., Jones CK; 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., Conn PJ; 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.; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States., Lindsley CW; 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.; Department of Chemistry, Vanderbilt University, Nashville Tennessee 37232, United States.; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical neuroscience [ACS Chem Neurosci] 2025 Jan 01; Vol. 16 (1), pp. 95-107. Date of Electronic Publication: 2024 Dec 11.
DOI:	10.1021/acschemneuro.4c00769
Abstrakt:	Herein we detail the first disclosure of VU0467319 (VU319), an M 1 Positive Allosteric Modulator (PAM) clinical candidate that successfully completed a Phase I Single Ascending Dose (SAD) clinical trial. VU319 ( 16 ) is a moderately potent M 1 PAM (M 1 PAM EC 50 = 492 nM ± 2.9 nM, 71.3 ± 9.9% ACh Max), with minimal M 1 agonism (EC 50 > 30 μM), that displayed high CNS penetration ( K p s > 0.67 and K p,uu s > 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 1 muscarinic receptors without eliciting cholinergic AEs that have plagued other drugs targeting CNS cholinergic neurotransmission.
Databáze:	MEDLINE
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