title: Synthesis and pharmacological evaluation of a series of new 3-methyl-1,4-disubstituted-piperidine analgesics.
abstract: The synthesis and intravenous analgesic activity of a series of 3-methyl-4-(N-phenyl amido)piperidines, entries 34-79, is described. The methoxyacetamide pharmacophore produced a series of compounds with optimal analgesic potency and short duration of action. cis-42 was 13,036 times more potent than morphine and 29 times more potent than fentanyl; however, the corresponding diastereomer 43 was only 2778 and 6 times more potent, respectively. Compounds 40, 43, 47, and 57 are extremely short acting; all had durations of action of about 2 min, which was about 1/5 of that of fentanyl in the mouse hot-plate test at a dose equivalent to 2 times the ED50 analgesic dose. Among the many compounds that displayed exceptional analgesic activity, duration of action was one of the main factors for choosing a candidate for further pharmacological investigation. At present, cis-1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-3-meth yl-4- [N-in equilibrium 2-fluorophenyl)methoxyacetamido]piperidine hydrochloride (40) (Anaquest, A-3331.HCl, Brifentanil) is in clinical evaluation. Opiate analgesics that possess short duration of action are excellent candidates for short surgical procedures in an outpatient setting where a rapid recovery is required.
authors.affiliation: Anaquest Pharmaceuticals, BOC Technical Center, Murray Hill, New Jersey 07974.
authors.forename: N
authors.initials: N
authors.lastname: Lalinde
authors.forename: J
authors.initials: J
authors.lastname: Moliterni
authors.forename: D
authors.initials: D
authors.lastname: Wright
authors.forename: H K
authors.initials: HK
authors.lastname: Spencer
authors.forename: M H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: T C
authors.initials: TC
authors.lastname: Spaulding
authors.forename: F G
authors.initials: FG
authors.lastname: Rudo
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005283:Fentanyl / Q000494:pharmacology; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000700:Analgesics; D010880:Piperidines; D011957:Receptors, Opioid; D013777:Tetrazoles; D009270:Naloxone; C065913:Brifentanil; D009020:Morphine; D005283:Fentanyl