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

Felts AS, Bollinger KA, Brassard CJ, Rodriguez AL, Morrison RD, Scott Daniels J, Blobaum AL, Niswender CM, Jones CK, Conn PJ, Emmitte KA, Lindsley CW
Bioorg Med Chem Lett. 2019 29 (1): 47-50

PMID: 30446311 · PMCID: PMC6295259 · DOI:10.1016/j.bmcl.2018.11.017

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.

Copyright © 2018 Elsevier Ltd. All rights reserved.

MeSH Terms (11)

Allosteric Regulation Animals Dose-Response Relationship, Drug Drug Discovery Humans Ligands Molecular Structure Picolinic Acids Rats Receptor, Metabotropic Glutamate 5 Structure-Activity Relationship

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