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

• Published in: Bioorganic & medicinal chemistry 2008-08, Vol.18 (15), p.4424-4427
• Main Authors: Lee, Hyung Kook, Lee, Yun Suk, Roh, Eun Joo, Rhim, Hyewhon, Lee, Jae Yeol, Shin, Kye Jung
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Calcium Channels, T-Type - drug effects; Cardiovascular system; Combinatorial Chemistry Techniques; Disease Models, Animal; Drug Design; Medical sciences; Mibefradil - pharmacology; Mice; Miscellaneous; Molecular Structure; Neuropathic pain; Patch-clamp; Pharmacology. Drug treatments; Phenylacetates - chemical synthesis; Phenylacetates - chemistry; Phenylacetates - pharmacology; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; T-type calcium channel
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.06.037

Novel series of α,α′-disubstituted phenylacetate derivatives ( 10 and 11) based on pharmacophore mapping study were prepared and evaluated for T-type calcium channel (α 1G) 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. We have synthesized and evaluated α,α′-disubstituted phenylacetate derivatives that were designed as T-type calcium channel blockers. Among them, compound 10e (IC 50 = 8.17 ± 0.48 nM) showed the most potent T-type calcium current blocking activity and higher potency than Mibefradil (IC 50 = 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.