GRC-17536

TRPA1 is a non-selective cation channel predominantly expressed in sensory neurons, and functions as an irritant sensor for a plethora of noxious external stimuli and endogenous ligands. Due to its involvement in pain, itch, and respiratory syndromes, TRPA1 has been pursued as a promising drug target.

In this review, the small molecule patent literature of TRPA1 antagonists from 2015-2019 was surveyed. The patent applications are described with a focus on chemical structures, biochemical/pharmacological activities, and potential clinical applications. The development of TRPA1 antagonists in clinical trials has been highlighted.

During 2015-2019, significant progress was made toward the discovery of new TRPA1 antagonists. A total of 14 organizations published 28 patent applications disclosing several distinct classes of chemical matter and potential uses. During this period, three new molecules entered the clinic (ODM-108, HX-100, and GDC-0334) bringing the total number of TRPA1 antagonists to reach clinical trials to five (including earlier molecules CB-625 and GRC 17536); however, to our knowledge, development of all five molecules have been discontinued. Further clinical trials of recent TRPA1 antagonists with good pharmacokinetics would be needed to help understand TRPA1 involvement in human diseases and its potential as a therapeutic target.

TRPA1 is a well-validated therapeutic target in areas of high unmet medical need that include pain and respiratory disorders. The human genetic rationale for TRPA1 as a pain target is provided by a study describing a rare gain-of-function mutation in TRPA1, causing familial episodic pain syndrome. There is a growing interest in the TRPA1 field, with many pharmaceutical companies reporting the discovery of TRPA1 chemical matter; however, GRC 17536 remains to date the only TRPA1 antagonist to have completed Phase IIa studies. A key issue in the progression of TRPA1 programmes is the identification of high-quality orally bioavailable molecules. Most published TRPA1 ligands are commonly not suitable for clinical progression due to low lipophilic efficiency and/or poor absorption, distribution, metabolism, excretion and pharmaceutical properties. The recent TRPA1 cryogenic electron microscopy structure from the Cheng and Julius labs determined the structure of full-length human TRPA1 at up to 4Å resolution in the presence of TRPA1 ligands. This ground-breaking science paves the way to enable structure-based drug design within the TRPA1 field.