title: 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.
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.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105, USA. lain.yen.hu@wl.com
authors.forename: L Y
authors.initials: LY
authors.lastname: Hu
authors.forename: T R
authors.initials: TR
authors.lastname: Ryder
authors.forename: M F
authors.initials: MF
authors.lastname: Rafferty
authors.forename: C P
authors.initials: CP
authors.lastname: Taylor
authors.forename: M R
authors.initials: MR
authors.lastname: Feng
authors.forename: B S
authors.initials: BS
authors.lastname: Kuo
authors.forename: S M
authors.initials: SM
authors.lastname: Lotarski
authors.forename: G P
authors.initials: GP
authors.lastname: Miljanich
authors.forename: E
authors.initials: E
authors.lastname: Millerman
authors.forename: K M
authors.initials: KM
authors.lastname: Siebers
authors.forename: B G
authors.initials: BG
authors.lastname: Szoke
mesh_terms: 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
chemical_list: 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