TRPV4 antagonists: a patent review (2015–2020)

ABSTRACT

Introduction: Transient receptor potential vanilloid 4 (TRPV4) is an ion channel that is widely expressed and is activated by numerous chemical, osmotic and mechanical stimuli. By modulating Ca²⁺ entry, TRPV4 regulates cellular signaling associated with a variety of (patho)physiological processes and is a target of interest for treatment of human diseases including heart failure, respiratory diseases, gastrointestinal disorders, dermatological conditions, pain and cancer, among others.

Areas covered: This article reviews small molecule TRPV4 antagonists and new therapeutic use claims disclosed in the patent literature from 2015 to 2020, including applications covering the first potent and selective TRPV4 clinical candidate and other advanced chemotypes.

Expert opinion: TRPV4 has proven to be a tractable target and significant progress in discovery of TRPV4 antagonists has been realized in recent years. Several unique chemical templates with drug-like properties inhibit the channel and show efficacy in models that suggest their potential for treatment of a variety of diseases. While compelling clinical efficacy has not yet been seen in the limited early studies conducted with GSK2798745, evaluation of TRPV4 antagonists in larger trials across several indications is warranted given the availability of high-quality candidates and the promise of therapeutic benefit based on pre-clinical evidence.

KEYWORDS:

• TRPV4
• antagonists
• GSK2798745
• edema
• heart failure
• pain

Article highlights

• TRPV4 is an ion channel involved in sensory response that is activated by a variety of environmental stimuli and is a therapeutic target for the treatment of numerous diseases.

• To date, a single TRPV4 antagonist, GSK2798745, has entered clinical trials showing limited pharmacodynamic activity in small numbers of healthy participants and heart failure and chronic cough subjects.

• Given the positive preclinical pharmacology of TRPV4 antagonists, further investigation in human disease may realize a therapeutic benefit for patients in areas such as pain, macular edema, dermatological disorders, hydrocephalus, spinal cord injury, and cancer.

• Interest in developing TRPV4 antagonists remains high, with 28 patent applications appearing from 2015–2020 from 12 different organizations covering 8 unique chemotypes.

This box summarizes key points contained in the article.

Abbreviations

4α-PDD, 4α-phorbol 12, 13-didecanoate; ARDS, acute respiratory distress syndrome; DL_CO, lung diffusing capacity for carbon monoxide; FaSSIF, fasted state simulated intestinal fluid; FLIPR^TM, flourescence imaging plate reader; F_po, oral bioavailability; GSK634775, N-((S)-1-(((R)-1-((2-cyanophenyl)sulfonyl)-3-oxoazepan4-yl)amino)-4-methyl-1-oxopentan-2-yl)benzo[b]thiophene-2-carboxamide; LPS, lipopolysaccharide; MRT, mean residence time; PKPD, pharmacokinetic-pharacodynamic; TRP, transient receptor potential; TRPV4, Transient receptor potential subfamily vanilloid member 4.

Declaration of interest

The authors are employees and own shares of GlaxoSmithKline. 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.

Additional information

Funding

This paper was not funded.