Lead discovery and optimization of T-type calcium channel blockers

Bioorg Med Chem. 2007 Feb 1;15(3):1409-19. doi: 10.1016/j.bmc.2006.11.004.

Jung Hwan Park ¹, Jin Kyu Choi, Eunjung Lee, Jae Kyun Lee, Hyewhon Rhim, Seon Hee Seo, Yoonjee Kim, Munikumar Reddy Doddareddy, Ae Nim Pae, Jahyo Kang, Eun Joo Roh

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Affiliation

1 Life Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.

PMID: 17150365 DOI: 10.1016/j.bmc.2006.11.004

Abstract

A series of compounds were designed as T-type calcium channel blocker containing 6 or 5 pharmacophore features from structure-based virtual screening. To optimize the suggested structure, over 130 derivatives were synthesized and their inhibitory activities on T-type calcium channel were assayed using in vitro screening system with alpha1(G) and alpha1(H) clones. For the compounds with higher activities in FDSS assay system, the efficacy was measured by patch-clamp method. Among the library with 5 features, alkaneamide derivatives (7b, 9j, 11b, 11g, 11h) with 4-arylsubstituted piperazine showed better IC(50) values than Mibefradil.

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