The discovery of VU0486846: steep SAR from a series of M1 PAMs based on a novel benzomorpholine core

被引：11

作者：

Bertron, Jeanette L. ^{[1
,3
]}

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

Garcia-Barrantes, Pedro M. ^{[1
,3
]}

Panarese, Joseph D. ^{[1
,2
]}

Salovich, James M. ^{[1
,2
]}

Nance, Kellie D. ^{[1
,2
]}

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

Rook, Jerri M. ^{[1
,2
]}

Blobaum, Anna L. ^{[1
,2
]}

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

Stauffer, Shaun R. ^{[1
,2
,3
]}

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

Lindsley, Craig W. ^{[1
,2
,3
,4
]}

机构：

[1] Vanderbilt Univ, Med Ctr, 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] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 12期

关键词：

M-1; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure-Activity Relationship (SAR); POSITIVE ALLOSTERIC MODULATORS; DRUG DISCOVERY; SCHIZOPHRENIA; OPPORTUNITIES; OPTIMIZATION; IMPAIRMENTS; RECEPTORS; DESIGN;

D O I：

10.1016/j.bmcl.2018.05.009

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 new series of M-1 positive allosteric modulators (PAMs) based on a novel benzomorpholme core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).

引用

页码：2175 / 2179

页数：5

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