Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel K_Ca3.1.

ABSTRACT: The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K⁺ channel K_Ca3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K_Ca3.1 with an IC₅₀ of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of >100 addi

SUBMITTER: Ong ST 

PROVIDER: S-EPMC12067266 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature