June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
TRPM8 Agonists: A New Approach to Dry Eye Disease Treatment
Author Affiliations & Notes
  • Mitchell A. deLong
    Chemistry, Duke University, Durham, North Carolina, United States
    Chemistry, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Curtis R. Kelly
    Biology, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Jill Sturdivant
    Chemistry, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Heeren Gordhan
    Chemistry, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Cynthia L. Lichorowic
    Chemistry, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • David A. Ellis
    Biology, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Casey C Kopczynski
    Biology, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Footnotes
    Commercial Relationships   Mitchell deLong Aerie Pharmaceuticals, Code E (Employment), Alcon , Code E (Employment); Curtis Kelly Aerie Pharmaceuticals, Alcon, Code E (Employment); Jill Sturdivant Aerie Pharmaceuticals, Alcon, Code E (Employment); Heeren Gordhan Aerie Pharmaceuticals, Alcon, Code E (Employment); Cynthia Lichorowic Aerie Pharmaceuticals, Alcon, Code E (Employment); David Ellis Aerie Pharmaceuticals, Alcon, Code E (Employment); Casey Kopczynski Aerie Pharmaceuticals, Alcon, Code E (Employment)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 744. doi:
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      Mitchell A. deLong, Curtis R. Kelly, Jill Sturdivant, Heeren Gordhan, Cynthia L. Lichorowic, David A. Ellis, Casey C Kopczynski; TRPM8 Agonists: A New Approach to Dry Eye Disease Treatment. Invest. Ophthalmol. Vis. Sci. 2023;64(8):744.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : AR-15512, (1R,2S,5R)-N-(4-methoxyphenyl)-p-menthane carboxamide), a small molecule in Phase 3 clinical trials for treating Dry Eye disease, is a potent and long-lasting transient receptor potential melastatin 8 (TRPM8) ligand agonist. Agonists and antagonists of the TRP family of ion channels are only now gaining attention in the treatment of ocular disease. This research was designed to better understand the activity of agonists of the TRPM8 ion channel, and to explore SAR around ‘512 providing backup molecules with potentially better profiles.

Methods : All molecules were synthesized in-house at Aerie Pharmaceuticals, Inc. (Durham, NC) now Alcon, from readily available starting materials. Agonist and antagonist compounds were evaluated for functional activity at the human TRPM8 or TRPV1 ion channels using TRP cellular assays conducted at Eurofins (Eurofins, France). Graphs and statistics were created using GraphPad Prism™

Results : AR-15512 and the known ligand icilin were shown to be potent agonists of TRPM8 with EC50 values of 24 and 28 nM, respectively. Menthol was shown to be a weak agonist under these conditions. Novel compounds were also synthesized, that demonstrated a range of activities, from partial agonism to super agonism, with the largest having 120% of the signal created by icilin agonism. Compounds also were tested over a wide range of concentrations for agonist and antagonist activity against the TRPV1 channel, which mediates heat sensation and pain.

Conclusions : Multiple promising candidates have been identified as potential backup or next generation ligands of this pathway. Work continues to identify novel ligands of the TRP family of ion channels and to build the SAR thereof.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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