Design, synthesis and biological activity of amidinobicyclic compounds (derivatives of DX-9065a) as factor Xa inhibitors: SAR study of S1 and aryl binding sites

Compound 38 exhibited a high activity toward factor Xa and also showed prolongation of APTT after oral administration in rat. Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2004-05, Vol.12 (9), p.2099-2114
Main Authors: Komoriya, Satoshi, Kanaya, Naoaki, Nagahara, Takayasu, Yokoyama, Asako, Inamura, Kazue, Yokoyama, Yukio, Katakura, Shin-ichi, Hara, Tsuyoshi
Format: Article
Language:English
Subjects:
Animals
Anticoagulants - chemical synthesis
Anticoagulants - chemistry
Anticoagulants - pharmacology
Binding Sites
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Factor Xa Inhibitors
Magnetic Resonance Spectroscopy
Male
Medical sciences
Naphthalenes - chemical synthesis
Naphthalenes - chemistry
Naphthalenes - pharmacology
Pharmacology. Drug treatments
Propionates - chemical synthesis
Propionates - chemistry
Propionates - pharmacology
Rats
Rats, Wistar
Spectrometry, Mass, Fast Atom Bombardment
Structure-Activity Relationship
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Summary:Compound 38 exhibited a high activity toward factor Xa and also showed prolongation of APTT after oral administration in rat. Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2 S)-2-[4-[[(3 S)-1-Acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (DX-9065a) was previously found in our laboratory as a novel orally active factor Xa inhibitor. DX-9065a exhibits a strong inhibitory activity toward fXa by occupying the substrate recognition (called S1) sites and aryl binding sites of fXa. Herein we describe conversions of the amidinonaphthalene and the acetimidoylpyrrolidine moieties of DX-9065a. Some compounds showed remarkably increased in vitro anti-factor Xa and PRCT activities compared with those of DX-9065a. The most promising compound 38 showed four times the prolongation of APTT against DX-9065a after oral administration to rats.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2004.02.032