Optimization of M4 positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology

被引：22

作者：

Melancon, Bruce J. ^{[1
,2
]}

Wood, Michael R. ^{[1
,3
]}

Noetzel, Meredith J. ^{[1
,2
]}

Nance, Kellie D. ^{[1
]}

Engelberg, Eileen M. ^{[1
]}

Han, Changho ^{[1
]}

Lamsal, Atin ^{[1
]}

Chang, Sichen ^{[1
]}

Cho, Hyekyung P. ^{[1
,2
]}

Byers, Frank W. ^{[1
]}

Bubser, Michael ^{[1
]}

Jones, Carrie K. ^{[1
,2
,5
]}

Niswender, Colleen M. ^{[1
,2
,5
]}

Wood, Michael W. ^{[4
]}

Engers, Darren W. ^{[1
,2
]}

Wu, Dedong ^{[6
]}

Brandon, Nicholas J. ^{[4
]}

Duggan, Mark E. ^{[4
]}

Conn, Jeffrey ^{[1
,2
,5
]}

Bridges, Thomas M. ^{[1
,2
]}

Lindsley, Craig W. ^{[1
,2
,3
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[4] AstraZeneca, Neurosci Innovat Med & Early Dev, Waltham, MA 02451 USA

[5] Vanderbilt Univ, Sch Med, Vanderbilt Kennedy Ctr, Nashville, TN 37232 USA

[6] AstraZeneca, Pharmaceut Sci, 35 Gatehouse Dr, Waltham, MA 02451 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 11期

关键词：

M-4; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Non-human primate (NHP); Structure-Activity Relationship (SAR); MUSCARINIC ACETYLCHOLINE-RECEPTOR; SCHIZOPHRENIA; POTENTIATORS; CHALLENGES; SERIES; CORE;

D O I：

10.1016/j.bmcl.2017.04.043

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This letter describes the further chemical optimization of the 5-amino-thieno(2,3-c]pyridazine series (VU0467154/VU0467485) of M-4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：2296 / 2301

页数：6

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