Synthesis and evaluation of α,α′-disubstituted phenylacetate derivatives for T-type calcium channel blockers

We have synthesized and evaluated α,α′-disubstituted phenylacetate derivatives that were designed as T-type calcium channel blockers. Among them, compound 10e (IC50 = 8.17 ± 0.48 nM) showed the most potent T-type calcium current blocking activity and higher potency than Mibefradil (IC50 = 1.34 ± 0.49 μM). The PK profile and subtype selectivity over L-type calcium channel were satisfied for further animal assay using disease model.

Graphical abstractNovel series of α,α′-disubstituted phenylacetate derivatives (10 and 11) based on pharmacophore mapping study were prepared and evaluated for T-type calcium channel (α1G) blockers by patch-clamp method. Among them, compound 10e (X = p-Br, Y = H, R = Me) showed higher potency than Mibefradil and competitive PK profiles for further in vivo assay.Figure optionsDownload full-size imageDownload as PowerPoint slide