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Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Jan 01; Vol. 29 (1), pp. 47-50. Date of Electronic Publication: 2018 Nov 10. - Publication Year :
- 2019
-
Abstract
- This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu <subscript>5</subscript> 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 <superscript>3</superscript> character, uniform CYP <subscript>450</subscript> -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.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Allosteric Regulation drug effects
Animals
Dose-Response Relationship, Drug
Humans
Ligands
Molecular Structure
Picolinic Acids chemical synthesis
Picolinic Acids chemistry
Rats
Receptor, Metabotropic Glutamate 5 metabolism
Structure-Activity Relationship
Drug Discovery
Picolinic Acids pharmacology
Receptor, Metabotropic Glutamate 5 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 29
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 30446311
- Full Text :
- https://doi.org/10.1016/j.bmcl.2018.11.017