Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 68, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2022.128763
Keywords
Endocannabinoid system; Peripheral; FAAH; MAGL; Inhibitor; Topological polar surface area
Categories
Funding
- Liberty University Center for Research and Scholarship [PRI1931, UG2118]
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A small library of FAAH and dual FAAH/MAGL inhibitors designed for peripheral selectivity were studied. Three compounds with desirable FAAH inhibition and reduced permeability were identified. Further assays confirmed that one compound was a relative selective FAAH inhibitor, while the other one exhibited characteristics of a true dual enzyme inhibitor.
A small library of FAAH and dual FAAH/MAGL inhibitors designed for peripheral selectivity were targeted. Of these compounds, three were identified to have desirable FAAH inhibition and reduced permeability in a PAMPA assay. Those three compounds were advanced into a MAGL inhibitor assay and one was found to be a relative selective FAAH inhibitor, FAAH to MAGL IC50 ratio of 1:27, and one was found to be more characteristic of a true dual enzyme inhibitor, FAAH to MAGL IC50 ratio of 1:4. Both compounds showed activity in an ABPP assay, blockage of TAMRA-FP labeling of FAAH and MAGL in rat eye homogenate.
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