Caspase inhibitors: a review of recently patented compounds (2013-2015)

ABSTRACT

Introduction: Although many caspase inhibitors have been patented, caspase inhibitors have not entered the market due to their toxicity and poor pharmacokinetic profile.

Areas covered: In this article, we review patents (2013–2015) for peptide and non-peptide caspase inhibitors and their compositions.

Expert opinion: Noteworthy patents include a peptidic caspase-2 inhibitor for nasal administration and a peptidomimetic caspase-6 inhibitor that can be administered via several routes for the treatment of neurodegenerative diseases. Furthermore, caspase-1 inhibitors for contact dermatitis and inflammation, cardiovascular diseases, and liver diseases and a caspase-3 inhibitor for cerebral stroke have been patented. Of particular interest is the novel use of tyrosine kinase inhibitors (sunitinib and its derivatives) for the prevention and treatment of age-related ocular diseases via inhibition of the caspase-3, dual-leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) pathways. However, for effective clinical application of caspase inhibitors, novel peptidic and nonpeptidic caspase inhibitors with lower toxicity and improved efficacy should be developed via structural modifications, and further animal studies and preclinical and clinical trials are needed. In addition, the poor pharmacokinetic properties of classic caspase inhibitors may be improved by using advanced drug delivery systems that employ liposomes, polymers, and nanoparticles through effective administration routes.

KEYWORDS:

• Peptide caspase inhibitors
• apoptosis
• cardiovascular disease
• neurodegenerative disease
• immune disorders
• liver diseases
• glaucoma
• administration routes

Article highlights

• Peptidic caspase-2 and caspase-6 inhibitors and calpain peptidomimetic inhibitors for neurodegenerative diseases.

• Synthetic caspase inhibitors based on 2-[(4-formyl-pyrazol-5-yl)-thio]acetic acid derivatives to improve pharmacological properties for the treatment of AD.

• Caspase-1 inhibitor for contact dermatitis and caspase 6 inhibitor for graft rejection.

• Sunitinib and other TKIs for the prevention or treatment of ocular-related neurodegenerative diseases including glaucoma by inhibition of caspase-3-, DLK- and/or LZK-related pathways.

• For practical application of patented caspase inhibitors, further animal and preclinical studies and clinical trials are required.

• Advanced drug delivery systems can be introduced to classic caspase inhibitors to improve poor pharmacokinetic issues using liposomes, polymers, and nanoparticles through effective administration routes.

This box summarizes key points contained in the article.

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 work was supported by a Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean government (MEST) (2014R1A2A10052872).