Discovery of novel tetrahydroisoquinoline derivatives as potent and selective factor Xa inhibitors

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

doi:10.1016/j.bmcl.2004.10.033

Discovery of novel tetrahydroisoquinoline derivatives as potent and selective factor Xa inhibitors

Bioorg Med Chem Lett. 2005 Jan 3;15(1):185-9. doi: 10.1016/j.bmcl.2004.10.033.

Authors

Hiroshi Ueno¹, Katsuyuki Yokota, Jun-ichi Hoshi, Katsutaka Yasue, Mikio Hayashi, Itsuo Uchida, Kazuo Aisaka, Yasunori Hase, Susumu Katoh, Hidetsura Cho

Affiliation

¹ Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.

PMID: 15582437
DOI: 10.1016/j.bmcl.2004.10.033

Abstract

A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 (JTV-803) exhibited potent inhibitory activity against 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 monkey, and showed a dose-dependent antithrombotic effect in a rat model of venous thrombosis.

MeSH terms

Animals
Factor Xa Inhibitors*
Rats
Serine Proteinase Inhibitors / pharmacology*
Serine Proteinase Inhibitors / therapeutic use
Tetrahydroisoquinolines / pharmacology*
Tetrahydroisoquinolines / therapeutic use
Venous Thrombosis / drug therapy
Venous Thrombosis / enzymology

Substances

Factor Xa Inhibitors
Serine Proteinase Inhibitors
Tetrahydroisoquinolines