Challenges in the development of an M4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs

被引：29
作者：
Wood, Michael R. [1 ,3 ]
Noetzel, Meredith J. [1 ,2 ]
Poslusney, Michael S. [1 ]
Melancon, Bruce J. [1 ,2 ]
Tarr, James C. [1 ]
Lamsal, Atin [1 ]
Chang, Sichen [1 ]
Luscombe, Vincent B. [1 ,2 ]
Weiner, Rebecca L. [1 ,2 ]
Cho, Hyekyung P. [1 ,2 ]
Bubser, Michael [1 ]
Jones, Carrie K. [1 ,2 ,5 ]
Niswender, Colleen M. [1 ,2 ,5 ]
Wood, Michael W. [4 ]
Engers, Darren W. [1 ,2 ]
Brandon, Nicholas J. [4 ]
Duggan, Mark E. [4 ]
Conn, P. 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] Astra Zeneca, Neurosci Innovat Med, 141 Portland St, Cambridge, MA 02139 USA
[5] Vanderbilt Univ, Vanderbilt Kennedy Ctr, Sch Med, Nashville, TN 37232 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 02期
关键词：
M-4; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure-activity relationship (SAR); MUSCARINIC ACETYLCHOLINE-RECEPTOR; POSITIVE ALLOSTERIC MODULATOR; SCHIZOPHRENIA; POTENTIATORS; SERIES; CORE;
D O I：
10.1016/j.bmcl.2016.11.086
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
This letter describes the chemical optimization of a novel series of M-4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration). (C) 2016 Elsevier Ltd. All rights reserved.
引用
收藏
页码：171 / 175
页数：5
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