Lead discovery and optimization of T-type calcium channel blockers.
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.
Park
Jung Hwan
JH
Life Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
Choi
Jin Kyu
JK
Lee
Eunjung
E
Lee
Jae Kyun
JK
Rhim
Hyewhon
H
Seo
Seon Hee
SH
Kim
Yoonjee
Y
Doddareddy
Munikumar Reddy
MR
Pae
Ae Nim
AN
Kang
Jahyo
J
Roh
Eun Joo
EJ
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
D000473:Alkanes; D000577:Amides; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010879:Piperazines; D020748:Mibefradil; D002118:Calcium