Recent Progress in the Discovery and Development of TRPA1 Modulators.
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.
Convergence (a Biogen Company), Cambridge, United Kingdom.
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D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D055808:Drug Discovery; D006801:Humans; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000187:drug effects*
D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels
GRC 17536; Inflammatory pain; Migraine; Neuropathic pain; Respiratory disorders; Single-particle electron cryomicroscopy; TRPA1; TRPA1 medicinal chemistry; TRPA1 safety; Transient receptor potential ankyrin