T-type calcium channel blockers: a patent review (2012–2018)

ABSTRACT

Introduction: T-type calcium channels are attractive targets for potential treatment of epilepsy inflammatory or neuropathic pain, insomnia, Parkinson’s disease, and cancer. Three isoforms having different biophysical functions are expressed in peripheral and central nerve. Since the withdrawal of mibefradil, the first compound marketed for selective T-type calcium channel blockade, extensive efforts have been made to identify more selective T-type calcium channel blockers.

Areas covered: This review covers the 43 patents describing ‘organic small molecules as T-type calcium channel blockers’-published since 2012. The most recent similar patent review was published in 2011. Information from a recent review article and relevant research papers has been included, as well as biological data and clinical trial results where available.

Expert opinion: Triazinone derivatives, carbazole compounds, and aryl triazole/imidazole amide derivatives display potent blockade activity α1H, α1G, and pan T-type calcium channel subtypes, respectively, though the specificity of the letter is still unsatisfactory. Nonetheless, improvements seen in the efficacy of compounds targeting α1H T-type calcium channels indicate significant progress. Ongoing clinical trials are for the candidates Z944 (Phase II) and ACT-709478 (Phase II) appear promising. These studies may lead to a new generation of inhibitors with higher selectivity, improved physicochemical properties, and reduced side effects.

KEYWORDS:

• CNS-related disease
• epilepsy
• neuropathic pain
• selective T-type calcium channel blocker

Article highlights

• Regulation of neuronal T-type calcium channels is a promising strategy for the treatment of disorders related to neurodegenerative disease, including neuropathic or inflammatory pain, epilepsy, and cancer.

• Recent progress in the discovery of selective blockers for different calcium channels subtypes is very promising for the treatment of neuronal calcium channel-related diseases due to the widely differing contributions of each calcium channel subtype to the physiologies of neuronal cells.

• Numerous scientific efforts to develop subtype-selective T-type calcium channel blockers are underway. Considerable progress appears to have been made in the efficacy of α1H T-type calcium channel blockade.

• Clinical trials are currently ongoing for the promising candidates Z944 (Phase II) and ACT-709478 (Phase II).

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Declaration of interest

GN declares that they work for the Division of Bio-Medical Science, Korea Institutes of Science and Technology.

Reviewer disclosures

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

Additional information

Funding

This work is supported by the Original Technology Research Program (NRF-2016M3C7A1904344) and Brain research program ICT & Future Planning (NRF-2016M3C7A1913845) funded by the National Research Foundation of Korea (NRF). This work was also supported by Korea Institute of Science and Technology (Grant: 2E27870).