The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate

被引：7

作者：

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

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

Wu, Yong-Jin ^{[3
]}

Guernon, Jason M. ^{[3
]}

Chun, Aspen ^{[1
,2
]}

Gregro, Alison R. ^{[1
,2
]}

Bender, Aaron M. ^{[1
,2
]}

Capstick, Rory A. ^{[1
,2
]}

Wieting, Joshua M. ^{[1
,2
]}

Bronson, Joanne J. ^{[3
]}

Macor, John E. ^{[3
]}

Westphal, Ryan ^{[3
]}

Soars, Matthew ^{[3
]}

Engers, Julie E. ^{[1
,2
]}

Felts, Andrew S. ^{[1
,2
]}

Rodriguez, Alice L. ^{[1
,2
]}

Emmitte, Kyle A. ^{[1
,2
]}

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

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

Conn, P. Jeffrey ^{[1
,2
,6
]}

Niswender, Colleen M. ^{[1
,2
,6
]}

Hopkins, Corey R. ^{[1
,2
]}

Lindsley, Craig W. ^{[1
,2
,4
,5
]}

机构：

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

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

[3] Bristol Myers Squibb Co, Res & Dev, 5 Res Pkwy, Wallingford, CT 06492 USA

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

[5] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 02期

关键词：

mGlu(4); Metabotropic glutamate receptor; Positive allosteric modulator (PAM); Parkinson's disease (PD); Structure-activity relationship (SAR); POSITIVE ALLOSTERIC MODULATOR; MGLUR4; VU0418506; SERIES;

D O I：

10.1016/j.bmcl.2018.10.050

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu(4) positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).

引用

页码：342 / 346

页数：5

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