Evaluation of Synthetic Cytochrome P₄₅₀-Mimetic Metalloporphyrins To Facilitate "Biomimetic" Biotransformation of a Series of mGlu₅ Allosteric Ligands.

ABSTRACT: Allosteric ligands within a given chemotype can have the propensity to display a wide range of pharmacology, as well as unexpected changes in GPCR subtype selectivity, typically mediated by single-atom modifications to the ligand. Due to the unexpected nature of these "molecular switches", chemotypes with this property are typically abandoned in lead optimization. Recently, we have found that in vivo oxidative metabolism by CYP₄₅₀s can also engender molecular switches within allosteric ligands, changing the mode of pharmacology and leading to unwanted toxicity. We required a higher-throughput approach to assess in vivo metabolic molecular switches, and we turned to a "synthetic liver", a 96 well kit of biomimetic catalysts (e.g., metalloporphyrins) to rapidly survey a broad pane

SUBMITTER: Presley CC 

PROVIDER: S-EPMC6690571 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature