Synthesis and structure-activity relationships of novel selective factor Xa inhibitors with a tetrahydroisoquinoline ring.
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.
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
Hase
Yasunori
Y
Uchida
Itsuo
I
Aisaka
Kazuo
K
Katoh
Susumu
S
Cho
Hidetsura
H
D000284:Administration, Oral; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D002539:Cerebral Arterial Diseases / Q000150:complications; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008252:Macaca fascicularis; D020768:Middle Cerebral Artery; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020246:Venous Thrombosis / Q000188:drug therapy
C442639:4-((2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl)-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007546:Isoquinolines; D010880:Piperidines; D011725:Pyridines; D044005:Tetrahydroisoquinolines; D015951:Factor Xa