Synthesis and structure-activity relationships of novel selective factor Xa inhibitors with a tetrahydroisoquinoline ring

Hiroshi Ueno, Katsuyuki Yokota, Jun Ichi Hoshi, Katsutaka Yasue, Mikio Hayashi, Yasunori Hase, Itsuo Uchida, Kazuo Aisaka, Susumu Katoh, Hidetsura Cho

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17 Citations (Scopus)

Abstract

A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkeys, showed a dose-dependent antithrombotic effect at 0.1, 0.3, and 1 mg kg-1 h-1 in a rat model of venous thrombosis, and significantly reduced the size of brain infarction in a middle cerebral artery occlusion model at a dose of 0.1 mg kg-1 h-1. These results suggest that compound 2 (JTV-803) is likely to be useful as both a venous and arterial antithrombotic agent.

Original languageEnglish
Pages (from-to)3586-3604
Number of pages19
JournalJournal of Medicinal Chemistry
Volume48
Issue number10
DOIs
Publication statusPublished - 2005 May 19

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Ueno, H., Yokota, K., Hoshi, J. I., Yasue, K., Hayashi, M., Hase, Y., Uchida, I., Aisaka, K., Katoh, S., & Cho, H. (2005). Synthesis and structure-activity relationships of novel selective factor Xa inhibitors with a tetrahydroisoquinoline ring. Journal of Medicinal Chemistry, 48(10), 3586-3604. https://doi.org/10.1021/jm058160e