Transient receptor potential ankyrin 1 (TRPA1) antagonists: a patent review (2015–2019)

ABSTRACT

Introduction

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.

Areas covered

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.

Expert opinion

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.

KEYWORDS:

• Transient receptor potential ankyrin 1
• trpa1
• antagonist
• pain
• asthma

Article highlights

• TRPA1 remains an attractive target for pain, dermatological, and respiratory diseases based on genetic mutation, knock out animal studies, and preclinical and early phase clinical studies using small molecule TRPA1 antagonists.

• In this review, 28 patents of small molecule TRPA1 antagonists from 2015 to 2019 were surveyed and classified by organization. Both the generic Markush structures, representative examples, and associated biological data were described. Clinical trial information was described wherever applicable.

• While great progress has been made in the discovery of potent TRPA1 antagonists, the field is awaiting the ultimate success in the clinic.

• Future clinical trial results of diverse TRPA1 antagonists with improved pharmacokinetics will be necessary to help understand TRPA1 involvement in human diseases.

Acknowledgments

The authors would like to thank Dr. Mingshuo Zeng for her assistance in patent application translation, Dr. Matthew Volgraf and Dr. James J. Crawford for assistance in reviewing the manuscript, and Dr. Jun Chen and Dr. David H. Hackos for helpful discussions.

Declaration of interest

The authors are employees of Genentech, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.