title: Lead discovery and optimization of T-type calcium channel blockers.
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.
authors.affiliation: Life Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Park
authors.forename: Jin Kyu
authors.initials: JK
authors.lastname: Choi
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.forename: Jae Kyun
authors.initials: JK
authors.lastname: Lee
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Seo
authors.forename: Yoonjee
authors.initials: Y
authors.lastname: Kim
authors.forename: Munikumar Reddy
authors.initials: MR
authors.lastname: Doddareddy
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.forename: Jahyo
authors.initials: J
authors.lastname: Kang
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Roh
mesh_terms: D000473:Alkanes / Q000737:chemistry*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D015195:Drug Design; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects; D020748:Mibefradil / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D000473:Alkanes; D000577:Amides; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010879:Piperazines; D020748:Mibefradil; D002118:Calcium