Discovery of novel tetrahydroisoquinoline derivatives as potent and selective factor Xa inhibitors.
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.
Ueno
Hiroshi
H
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Yokota
Katsuyuki
K
Hoshi
Jun-ichi
J
Yasue
Katsutaka
K
Hayashi
Mikio
M
Uchida
Itsuo
I
Aisaka
Kazuo
K
Hase
Yasunori
Y
Katoh
Susumu
S
Cho
Hidetsura
H
D000818:Animals; D065427:Factor Xa Inhibitors; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D044005:Tetrahydroisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D020246:Venous Thrombosis / Q000188:drug therapy / Q000201:enzymology
D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D044005:Tetrahydroisoquinolines