Nilvadipine

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 Ca 3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K Ca 3.1 with an IC 50 of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of >100 additional molecular targets. Using high-resolution structure determination by cryogenic electron microscopy together with mutagenesis and electrophysiology, we delineated the drug binding pocket for DHP-103 within the water-filled central cavity of the K Ca 3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K Ca 3.1 channels that cause hereditary xerocytosis, suggesting its potential use as a therapeutic for this hemolytic anemia. In a rat model of acute ischemic stroke, the second leading cause of death worldwide, DHP-103 administered 12 h postischemic insult in proof-of-concept studies reduced infarct volume, improved balance beam performance (measure of proprioception) and decreased numbers of activated microglia in infarcted areas. K Ca 3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K Ca 3.1 has been experimentally confirmed as a therapeutic target.

Abraham solvation equation (Absolv) is a popular and well-established approach for modeling solute partitioning between phases of different polarity, which finds its applications in both organic chemistry and biomedical fields. Parameters constituting this equation are good quantitative descriptors of solute hydrogen bonding potential that are useful for QSAR modeling of more complex chemical and biological phenomena. Numerous studies dealing with fast determination of Abraham descriptors using HPLC can be found in the literature, but these mostly focus on small un-ionizable industrial and environmental chemicals, whereas experimental data for pharmaceutical molecules are clearly lacking. In the current study we build upon a previously published chromatographic approach, aiming to adapt the method to ionizable drug-like compounds, and optimize it by reducing the number of required HPLC columns. The analysis involves determination of the overall H-bond acidity (A), H-bond basicity (B) and polarity/polarizability (S) descriptors for 62 pharmaceutical molecules with previously unpublished parameter values.