Prodrug-based design, synthesis, and biological evaluation of N-benzenesulfonylpiperidine derivatives as novel, orally active factor Xa inhibitors.
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.
Ishihara
Tsukasa
T
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. tsukasa.ishihara@jp.astellas.com
Seki
Norio
N
Hirayama
Fukushi
F
Orita
Masaya
M
Koshio
Hiroyuki
H
Taniuchi
Yuta
Y
Sakai-Moritani
Yumiko
Y
Iwatsuki
Yoshiyuki
Y
Kaku
Seiji
S
Kawasaki
Tomihisa
T
Matsumoto
Yuzo
Y
Tsukamoto
Shin-ichi
S
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
D065427:Factor Xa Inhibitors; D011355:Prodrugs; D015842:Serine Proteinase Inhibitors