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

Authors

Felts AS Andrew S , Bollinger KA Katrina A , Brassard CJ Christopher J , Rodriguez AL Alice L , Morrison RD Ryan D , Scott Daniels J J , Blobaum AL Anna L , Niswender CM Colleen M , Jones CK Carrie K , Conn PJ P Jeffrey , Emmitte KA Kyle A , Lindsley CW Craig W .
Bioorganic & medicinal chemistry letters. 2018 11 10; 29(1).
47-50

Abstract

This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu 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 character, uniform CYP-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.

Tags: 2018