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
收藏
页码：47 / 50
页数：4
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