Aquaporin modulators: a patent review (2010–2015)

ABSTRACT

Introduction: Since the discovery of aquaporin-1 (AQP1) as a water channel, more than 2,000 articles, reviews and chapters have been published. The wide tissue expression, functional and biological roles have documented the major and essential physiological importance of these channels both in health and disease. Thus, over the years, studies have revealed essential importance of aquaporins in mammalian pathophysiology revealing aquaporins as potential drug targets.

Areas covered: Starting from a brief description of the main structural and functional features of aquaporins, their roles in physiology and pathophysiology of different human diseases, this review describes the main classes of small molecules and biologicals patented, published from 2010 to 2015, able to regulate AQPs for diagnostic and therapeutic applications.

Expert opinion: Several patents report on AQP modulators, mostly inhibitors, and related pharmaceutical formulations, to be used for treatments of water imbalance disorders, such as edema. Noteworthy, a unique class of gold-based compounds as selective inhibitors of aquaglyceroporin isoforms may provide new chemical tools for therapeutic applications, especially in cancer. AQP4-targeted therapies for neuromyelitis optica, enhancement of AQP2 function for nephrogenic diabetes insipidus and AQP1-5 gene transfer for the Sjogren’s syndrome represent promising therapies that deserve further investigation by clinical trials.

KEYWORDS:

• Aquaporins
• small-molecule inhibitors
• gold compounds
• biologicals
• cancer
• edema
• nephrogenic diabetes insipidus
• neuromyelitis optica

Article highlights

• Aquaporins (AQPs) are membrane channels involved in a wide range of physiological functions and human diseases. Modulators with confirmed selectivity, their pharmaceutical compositions and methods for use in diagnostic and treatment represent promising strategies for treatment of AQP-related pathologies.

• Compounds and methods for detecting and treating renal diseases and immune-inflammatory diseases such as neuromyetis optica (NMO) are the topic of numerous patent applications. Development of monoclonal antibodies or blockers of IgG-AQP4 will possibly be successful for prevention and treatment of NMO lesions.

• A number of patents describe small molecule AQPs modulators and pharmaceutical formulations for treatments of water imbalance disorders and edema. However, the selectivity of the modulators should be guaranteed to avoid side effects.

• Gold-based compounds showed selective inhibition of aquaglyceroporin isoforms and may be further optimized for pharmaceutical applications particularly for cancer treatment.

• Upregulation of AQP1, 2 and 5 may prove beneficial for treatment of loss-of-function aquaporin diseases such as renal disease, nephrogenic diabetes insipidus (NDI), salivary and lacrimal gland dysfunction, as well as obesity among others.

This box summarizes key points contained in the article.

Acknowledgments

EU COST Action CM1106 is acknowledged for promoting fruitful discussions. We thank P. Cardoso, Aexa Edea - Innovation and IP for technical advice.

Declaration of interest

The authors have no 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 partially funded by iMed.ULisboa (UID/DTP/04138/2013) from Fundação para a Ciência e a Tecnologia (FCT), Portugal.