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

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 1, 2005, Pages 185-189

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

^a JAPAN TOBACCO INC   (Japan)

Author keywords

Antithrombotic effect on venous thrombosis in rats; Inhibition of human FXa; JTV 803; Potent and selective factor Xa (FXa) inhibitor; Tetrahydroisoquinoline derivatives

Indexed keywords

4 [(2 AMIDINO 1,2,3,4 TETRAHYDRO 7 ISOQUINOLINYLOXY)METHYL] 1 (4 PYRIDINYL) 4 PIPERIDINECARBOXYLIC ACID; BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING FACTOR 10A INHIBITOR; PLASMIN; SERINE PROTEINASE; TETRAHYDROISOQUINOLINE DERIVATIVE; THROMBIN; TRYPSIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DISEASE MODEL; DOSE RESPONSE; DRUG ACTIVITY; DRUG DESIGN; DRUG EFFECT; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; INHIBITION KINETICS; MONKEY; NONHUMAN; RAT; VEIN THROMBOSIS;

ANIMALS; FACTOR XA; RATS; SERINE PROTEINASE INHIBITORS; TETRAHYDROISOQUINOLINES; VENOUS THROMBOSIS;

MACACA FASCICULARIS;

EID: 9644279535     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.10.033     Document Type: Article

References (19)

1. T. Hara, A. Yokoyama, H. Ishihara, Y. Yokoyama, and T. Nagahara Thromb. Haemost. 71 1994 314
2. T. Nagahara, Y. Yokoyama, K. Inamura, S. Katakura, S. Komoriya, H. Yamaguchi, T. Hara, and M. Iwamoto J. Med. Chem. 37 1994 1200
3. A. Betz Exp.Opin. Ther. Patents 11 2001 1007
4. R. Rai, P.A. Sprengeler, K.C. Elrod, and W.B. Young Curr. Med. Chem. 8 2001 101
5. W.R. Ewing, H.W. Pauls, and A.P. Spada Drugs Future 24 1999 771
6. B.Z. Zhu, and R.M. Scarborough Annu. Rep. Med. Chem. 35 2000 83
7. F. Hirayama, H. Koshio, T. Ishihara, S. Watanuki, S. Hachiya, H. Kaizawa, T. Kuramochi, N. Katayama, H. Kurihara, Y. Taniuchi, K. Sato, Y. Sakai-Moritani, S. Kaku, T. Kawasaki, Y. Matsumoto, S. Sakamoto, and S. Tsukamoto Bioorg. Med. Chem. 10 2002 2597
8. M.L. Quan, C.D. Ellis, M.Y. He, A.Y. Liauw, F.J. Woerner, R.S. Alexander, R.M. Knabb, P.Y.S. Lam, J.M. Luettgen, P.C. Wong, M.R. Wright, and R.R. Wexler Bioorg. Med. Chem. Lett. 13 2003 369
9. P.M. Hobbelen, T.G. van Dinther, G.M.T. Vogel, C.A.A. van Boeckel, H.C.T. Moelker, and D.G. Meuleman Thromb. Haemost. 63 1990 265
10. M.T. Stubbs, R. Huber, and W. Bode FEBS Lett. 375 1995 103
11. H. Brandstetter, A. Kuhne, W. Bode, R. Huber, W. von der Saal, K. Wirthensohn, and R.A. Engh J. Biol. Chem. 271 1996 29988
12. R. Kucznierz, F. Grams, H. Leinert, K. Marzenell, R.A. Engh, and W. von der Saal J. Med. Chem. 41 1998 4983
13. Katoh, S.; Yokota, K.; Hayashi, M., PCT Int. Appl. WO9952895, 1999
14. 99) favorably interacts with a positive charge. D.A. Dougherty Science 271 1996 163
15. H. Ueno, S. Katoh, K. Yokota, J. Hoshi, M. Hayashi, I. Uchida, K. Aisaka, Y. Hase, and H. Cho Bioorg. Med. Chem. Lett. 14 2004 4281
16. FXa-compound 1 complex model was built by docking compound 1 into the S1 and the aryl binding site on FXa crystal structure (PDB code 1fax). Discover and Insight II program from Accerlys were used for energy calculation and graphical displays, respectively
17. Ex vivo assessment of inhibition of human factor Xa in cynomolgus monkey plasma - Compound 2 was dissolved in physiological saline and was administrated intravenously to male cynomolgus monkeys at a dose of 1 mg/kg. Before administration and at 5, 10, 15, 30, 60, and 120 min after administration, 1500 μL blood samples were collected from the saphenous vein of each monkey into a syringe containing 300 μL of 3.8% citric acid. Plasma was prepared from each sample by centrifugation at 2000 × g for 10 min at 4°C. Compound 2 was dissolved in deionized distilled water and administered orally to fasting male cynomolgus monkeys at a dose of 10 mg/kg. Before administration and at 15, 30, 60, 120, 240, 360, and 480 min after oral administration, 1500 μL blood samples were collected and plasma was obtained as described above. Forty microliters of human factor Xa (0.5 U/mL) and 40 μL of a 4-fold diluted plasma sample were incubated in 40 μL of 0.1 M Tris-0.2 M NaCl buffer (pH 8.4) at 37°C for 10 min. Then, 40 μL of a synthetic substrate (S-2222, adjusted to 0.8 mM) was added and the mixture was incubated at 37°C for 3 min. The reaction was stopped by addition of 60% acetic acid and the absorbance at 405 nm was measured with a spectrometer (Model 3550, BIO-RAD, Hercules, USA). As the control, plasma obtained prior to administration of compound 2 was measured. Human factor Xa inhibitory activity was calculated as the percent inhibition relative to the control
18. 1/2 3.6 h, Bioavailability (B.A.) 10.7% (10 mg/kg po), Clearance 0.25 L/h/kg, Volume of Distribution 0.32 L/kg (1 mg/kg iv)
19. 3 was applied to the detached vein and removed after 20 min. Immediately after removing the filter paper, a 5 mm length of the abdominal vein was resected and weighed. The thrombus weight was calculated by subtracting the weight of the vessel walls from the total measured weight. Compound 2 (0.1, 0.3, 1 mg/kg/h) was administered by continuous intravenous infusion from 1 h prior to placement of the filter paper