Design and synthesis of endocannabinoid enzyme inhibitors for ocular indications

Alan Fulp; Sarah Bingham; Bethany Fisler; Felice Kho; Joshua Kim; So Jung Kim; Tabitha Martin; Bailey Mims; Kezia Reji Thomas; Grace Roe; Julia Spiotta; Julianna Young; Matthew Lazenka

doi:10.1016/j.bmcl.2022.128763

Design and synthesis of endocannabinoid enzyme inhibitors for ocular indications

Bioorg Med Chem Lett. 2022 Jul 15:68:128763. doi: 10.1016/j.bmcl.2022.128763. Epub 2022 Apr 29.

Authors

Affiliations

¹ Department of Biology and Chemistry, Liberty University, 1971 University Blvd, Lynchburg, VA 24515, USA. Electronic address: abfulp@liberty.edu.
² Department of Biology and Chemistry, Liberty University, 1971 University Blvd, Lynchburg, VA 24515, USA.
³ Kentucky College of Osteopathic Medicine and Kentucky College of Optometry, University of Pikeville, 147 Sycamore Street, Pikeville, KY 41501, USA.

PMID: 35500728
DOI: 10.1016/j.bmcl.2022.128763

Abstract

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.

Keywords: Endocannabinoid system; FAAH; Inhibitor; MAGL; Peripheral; Topological polar surface area.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amidohydrolases
Animals
Endocannabinoids*
Enzyme Inhibitors / pharmacology
Monoacylglycerol Lipases*
Rats

Substances

Endocannabinoids
Enzyme Inhibitors
Monoacylglycerol Lipases
Amidohydrolases