Binding mechanism investigations guiding the synthesis of novel condensed 1,4-dihydropyridine derivatives with L-/T-type calcium channel blocking activity

European Journal of Medicinal Chemistry
David SchallerGerhard Wolber

Abstract

Nifedipine and isradipine are prominent examples of calcium channel blockers with a 1,4-dihydropyridine (DHP) scaffold. Although successfully used in clinics since decades for the treatment of hypertension, the binding mechanism to their target, the L-type voltage-gated calcium channel Cav1.2, is still incompletely understood. Recently, novel DHP derivatives with a condensed ring system have been discovered that show distinct selectivity profiles to different calcium channel subtypes. This property renders this DHP class as a promising tool to achieve selectivity towards distinct calcium channel subtypes. In this study, we identified a common binding mode for prominent DHPs nifedipine and isradipine using docking and pharmacophore analysis that is also able to explain the structure-activity relationship of a small subseries of DHP derivatives with a condensed ring system. These findings were used to guide the synthesis of twenty-two novel DHPs. An extensive characterization using 1H NMR, 13C NMR, mass spectra and elemental analysis was followed by whole cell patch clamp assays for analyzing activity at Cav1.2 and Cav3.2. Two compounds were identified with significant activity against Cav1.2. Additionally, we identified four com...Continue Reading

Citations

May 28, 2019·International Journal of Molecular Sciences·Jiayi SunXingjie Guo
Oct 3, 2018·Current Medicinal Chemistry·Dan WangRichard J Lewis
Oct 16, 2018·Acta Crystallographica. Section E, Crystallographic Communications·Scott A SteigerNicholas R Natale
Nov 19, 2019·Mini Reviews in Medicinal Chemistry·Abhinav Prasoon MishraAwani Kumar Rai
Feb 20, 2020·Acta Crystallographica. Section E, Crystallographic Communications·Scott A SteigerNicholas R Natale
Dec 24, 2019·ACS Omega·Sandeep V H S BhaskaruniSreekantha B Jonnalagadda

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