Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

被引：5

作者：

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

Bollinger, Katrina A. ^{[1
,2
]}

Brassard, Christopher J. ^{[1
,2
]}

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

Morrison, Ryan D. ^{[1
,2
]}

Daniels, J. Scott ^{[1
,2
]}

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

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

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

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

Emmitte, Kyle A. ^{[1
,2
,5
,6
]}

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

机构：

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

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

[6] Univ North Texas Hlth Sci Ctr, UNT Syst Coll Pharm, Dept Pharmaceut Sci, 3500 Camp Bowie Blvd, Ft Worth, TX 76107 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 01期

关键词：

mGlu(5); Metabotropic glutamate receptor; Negative allosteric modulator (NAM); CNS; Structure-Activity Relationship (SAR); BASIMGLURANT; ANTAGONISTS; MGLU(5); POTENT; IDENTIFICATION; REINFORCEMENT; REINSTATEMENT; PHARMACOLOGY; MAVOGLURANT; VU0424238;

D O I：

10.1016/j.bmcl.2018.11.017

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 VU0424238 (auglurant), an mGlu(5) NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp(3) character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.

引用

页码：47 / 50

页数：4

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