Title of article :
The discovery of [1-(4-dimethylamino-benzyl)-piperidin-4-yl]-[4-(3,3-dimethylbutyl)-phenyl]-(3-methyl-but-2-enyl)-amine, an N-type Ca+2 channel blocker with oral activity for analgesia Original Research Article
Author/Authors :
Lain-Yen Hu، نويسنده , , Todd R. Ryder، نويسنده , , Michael F. Rafferty، نويسنده , , Charles P. Taylor، نويسنده , , M.Rose Feng، نويسنده , , Be-Sheng Kuo، نويسنده , , Susan M. Lotarski، نويسنده , , George P. Miljanich، نويسنده , , Elizabeth Millerman، نويسنده , , Krista M. Siebers، نويسنده , , Balazs G. Szoke، نويسنده ,
Abstract :
Our drug discovery efforts for N-type calcium channel blockers in the 4-piperidinylaniline series led to the discovery of an orally active analgesic agent 26. 1-[4-Dimethylamino-benzyl)-piperidin-4-yl]-[4-(3,3-dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-amine (26) showed high affinity to functionally block N-type calcium channels (IC50=0.7 μM in the IMR32 assay) and exhibited high efficacy in the anti-writhing analgesia test with mice (ED50=12 mg/kg by po and 4 mg/kg by iv). In this report, the rationale for the design, synthesis, biological evaluation, and pharmacokinetics of this series of blockers is described.
