Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides

被引：20

作者：

Tarr, James C. ^{[1
]}

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

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

Bertron, Jeanette L. ^{[1
]}

Weiner, Rebecca L. ^{[1
]}

Rodriguez, Alice L. ^{[1
]}

Lamsal, Atin ^{[1
]}

Byers, Frank W. ^{[1
,2
]}

Chang, Sichen ^{[1
,2
]}

Cho, Hyekyung P. ^{[1
]}

Jones, Carrie K. ^{[1
]}

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

Wood, Michael W. ^{[4
]}

Brandon, Nicholas J. ^{[4
]}

Duggan, Mark E. ^{[4
]}

Conn, P. Jeffrey ^{[1
]}

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

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

机构：

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

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

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

[4] Astra Zeneca, Neurosci Innovat Med, 141 Portland St, Cambridge, MA 02139 USA

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 13期

关键词：

M4; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Azetidine; MUSCARINIC ACETYLCHOLINE-RECEPTOR; POSITIVE ALLOSTERIC MODULATOR; SCHIZOPHRENIA; POTENTIATORS; COMPOUND; CORE;

D O I：

10.1016/j.bmcl.2017.05.014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c] pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and Pgp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3 mg/kg. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：2990 / 2995

页数：6

共 24 条

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