The discovery of [1-(4-dimethylamino-benzyl)-piperidin-4-yl]-[4-(3,3-dimethylbutyl)-phen yl]-(3-methyl-but-2-enyl)-amine, an N-type Ca+2 channel blocker with oral activity for analgesia

  • Bioorg Med Chem. 2000 Jun;8(6):1203-12. doi: 10.1016/s0968-0896(00)00077-8.
L Y Hu  1 ,  T R Ryder ,  M F Rafferty ,  C P Taylor ,  M R Feng ,  B S Kuo ,  S M Lotarski ,  G P Miljanich ,  E Millerman ,  K M Siebers ,  B G Szoke
Affiliations
  • 1. Department of Chemistry, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105, USA. [email protected]
PMID: 10896101 DOI: 10.1016/s0968-0896(00)00077-8
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-but yl)-phenyl]-(3-methyl-but-2-enyl)amine (26) showed high affinity to functionally block N-type calcium channels (IC50=0.7 microM 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.

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