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

Our drug discovery efforts for N-type calcium channel blockers in the 4-pip eridinylaniline series led to the discovery of an orally active analgesic a gent 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 functiona lly block N-type calcium channels IC50 = 0.7 mu M in the IMR32 assay) and e xhibited 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 seri es of blockers is described. (C) 2000 Elsevier Science Ltd. All rights rese rved.