Synthesis and evaluation of alpha,alpha'-disubstituted phenylacetate derivatives for T-type calcium channel blockers.
We have synthesized and evaluated alpha,alpha'-disubstituted phenylacetate derivatives that were designed as T-type calcium channel blockers. Among them, compound 10e (IC(50)=8.17+/-0.48nM) showed the most potent T-type calcium current blocking activity and higher potency than Mibefradil (IC(50)=1.34+/-0.49microM). The PK profile and subtype selectivity over L-type calcium channel were satisfied for further animal assay using disease model.
Lee
Hyung Kook
HK
Life Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongyang, Seoul 130-650, Republic of Korea.
Lee
Yun Suk
YS
Roh
Eun Joo
EJ
Rhim
Hyewhon
H
Lee
Jae Yeol
JY
Shin
Kye Jung
KJ
D000818:Animals; D001921:Brain / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D020650:Combinatorial Chemistry Techniques; D004195:Disease Models, Animal; D015195:Drug Design; D020748:Mibefradil / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010648:Phenylacetates; D010879:Piperazines; D020748:Mibefradil