title: Prodrug-based design, synthesis, and biological evaluation of N-benzenesulfonylpiperidine derivatives as novel, orally active factor Xa inhibitors.
abstract: We describe here our investigation of a new series of orally active fXa inhibitors based on a prodrug strategy. Solid-phase parallel synthesis identified a unique series of fXa inhibitors with a substituted benzenesulfonyl group as a novel S4 binding element. This series resulted in compound 39, which exhibited potent inhibitory activity against fXa (IC50 = 13 nM) and excellent selectivity over thrombin (>7000-fold). The masking of its highly hydrophilic groups led to the creation of related prodrug 28, which demonstrated an anticoagulant effect after oral dosing.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. tsukasa.ishihara@jp.astellas.com
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ishihara
authors.forename: Norio
authors.initials: N
authors.lastname: Seki
authors.forename: Fukushi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koshio
authors.forename: Yuta
authors.initials: Y
authors.lastname: Taniuchi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sakai-Moritani
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Iwatsuki
authors.forename: Seiji
authors.initials: S
authors.lastname: Kaku
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D065427:Factor Xa Inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D065427:Factor Xa Inhibitors; D011355:Prodrugs; D015842:Serine Proteinase Inhibitors