Potassium channels as drug targets for therapeutic intervention in respiratory diseases

Abstract

Background: Potassium channels represent a rich source of potential targets for therapeutic intervention. Clinically used potassium channel modulators comprise the sulfonylurea hypoglycemic agents (e.g., nateglinide, glipizide, mitiglinide), antiarrhythmic agents (dexsotalol, nifekalant, dofetilide, ibutilide), antianginal agents (nicorandil) and inotropic agents (levosimendan). Experimental evidence and preclinical models suggest the involvement of a number of potassium channels in respiratory diseases such as asthma and chronic obstructive pulmonary disease, supporting the prospects of potassium channel modulators as promising candidates in their therapeutic treatment. Objective: To present a survey on the most recent and relevant patents and patent applications of potassium channel modulators that have been claimed to be valuable for the treatment of chronic respiratory diseases: ATP-dependent K+ (KATP) channel openers, big-conductance K+ (BK) channel openers and intermediate-conductance K+ (IK) channel blockers. Methods: The review focuses on the most recent (January 2004 – June 2008) and relevant patents and patent applications in which respiratory diseases are included in the claims. Results/conclusion: KATP openers, the pioneer potassium channel modulators investigated for the treatment of respiratory diseases, are nowadays object of lesser attention by the pharmaceutical industry, probably due to lack of clinical success experienced by big Pharma in the face of the large medicinal chemistry efforts directed to identify airway-selective drugs. Emerging attention can instead be perceived in the patent literature for BKCa channel openers and their potential use for the same therapeutic indications. Preclinical data support this interest, although clinical proof of concept has not yet been obtained due to the lack of potent and selective BKCa drug candidates. This scenario may, however, change in the near future, given the claims of recently-synthesized BKCa openers superior to the benchmark NS1619. Until now, the only potassium channel modulating agent under clinical development in an airway indication is the IKCa1 channel blocker senicapoc (ICA-17043) from Icagen. This compound, which was investigated in Phase III trial for sickle cell anemia, is at present in Phase I for asthma.