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.
Alan Fulp  1 ,  Sarah Bingham  2 ,  Bethany Fisler  2 ,  Felice Kho  2 ,  Joshua Kim  2 ,  So Jung Kim  2 ,  Tabitha Martin  2 ,  Bailey Mims  2 ,  Kezia Reji Thomas  2 ,  Grace Roe  2 ,  Julia Spiotta  2 ,  Julianna Young  2 ,  Matthew Lazenka  3
Affiliations
  • 1. Department of Biology and Chemistry, Liberty University, 1971 University Blvd, Lynchburg, VA 24515, USA. Electronic address: [email protected].
  • 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.
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