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Recent Progress in the Discovery and Development of TRPA1 Modulators.

Authors
  • Skerratt, S1
  • 1 Convergence (a Biogen Company), Cambridge, United Kingdom. , (United Kingdom)
Type
Published Article
Journal
Progress in Medicinal Chemistry
Publisher
Elsevier
Publication Date
Jan 01, 2017
Volume
56
Pages
81–115
Identifiers
DOI: 10.1016/bs.pmch.2016.11.003
PMID: 28314413
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. © 2017 Elsevier B.V. All rights reserved.

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