Progress in Medicinal Chemistry by Unknown

Author:Unknown
Language: eng
Format: epub
ISBN: 9780444639431
Publisher: Elsevier Ltd.
Published: 2017-03-15T00:00:00+00:00

Chapter Three

Recent Progress in the Discovery and Development of TRPA1 Modulators

S. Skerratt Convergence (a Biogen Company), Cambridge, United Kingdom

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 4 Å resolution in the presence of TRPA1 ligands. This ground-breaking science paves the way to enable structure-based drug design within the TRPA1 field.

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