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 |
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Authors: | Hu L Y Ryder T R Rafferty M F Taylor C P Feng M R Kuo B S Lotarski S M Miljanich G P Millerman E Siebers K M Szoke B G |
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Institution: | Department of Chemistry, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105, USA. lain.yen.hu@wl.com |
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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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