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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

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 

[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

关键词: mGlu(5);    Metabotropic glutamate receptor;    Negative allosteric modulator (NAM);    CNS;    Structure-Activity Relationship (SAR);   

DOI  :  10.1016/j.bmcl.2018.11.017

来源: Elsevier

【 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.

【 授权许可】

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