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.
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.
Hu
L Y
LY
Department of Chemistry, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105, USA. lain.yen.hu@wl.com
Ryder
T R
TR
Rafferty
M F
MF
Taylor
C P
CP
Feng
M R
MR
Kuo
B S
BS
Lotarski
S M
SM
Miljanich
G P
GP
Millerman
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Siebers
K M
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Szoke
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D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D002460:Cell Line; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
C416379:(1-(4-dimethylaminobenzyl)piperidin-4-yl)-4((3,3-dimethylbutyl)phenyl)-(3-methylbut-2-enyl)amine; D000700:Analgesics; D000814:Aniline Compounds; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D010880:Piperidines