Development of trypsin-like serine protease inhibitors as therapeutic agents: Opportunities, challenges, and their unique structure-based rationales

Current Topics in Medicinal Chemistry

Volumn 16, Issue 13, 2016, Pages 1506-1529

  Liang, Guyan ^a   Bowen, J Phillip ^b  

^a SANOFI   (France)

^b MERCER UNIVERSITY   (United States)

Author keywords

Anticoagulants; Apixaban (Eliquis ); Catalytic triad (His57, Asp102, Ser195); Dabigatran etexikate (Pradaxa ); Edoxaban (Savaysa ); Factor IIa (fIIa) inhibitors; Factor VIa (fVIa) inhibitors; Factor Xa (fXa) inhibitors; Rivaroxaban (Xarelto ); Serine proteases; Stroke; Trypsin like serine proteases

Indexed keywords

ANTICOAGULANT AGENT; ANTIVITAMIN K; APIXABAN; DABIGATRAN ETEXILATE; EDOXABAN; HEPARIN; LOW MOLECULAR WEIGHT HEPARIN; NEW ORAL ANTICOAGULANT; PROTHROMBIN; RIVAROXABAN; SERINE PROTEINASE INHIBITOR; THROMBIN; THROMBIN INHIBITOR; TRYPSIN LIKE SERINE PROTEASE INHIBITOR; UNCLASSIFIED DRUG; WARFARIN; SERINE PROTEINASE; TRYPSIN-LIKE SERINE PROTEASE;

DRUG MONITORING; FOOD DRUG INTERACTION; PROCESS OPTIMIZATION; PROTEIN INTERACTION; REVIEW; BLOOD CLOTTING; CHEMISTRY; DRUG EFFECTS; HUMAN; METABOLISM; ORAL DRUG ADMINISTRATION; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ADMINISTRATION, ORAL; ANTICOAGULANTS; BLOOD COAGULATION; HUMANS; SERINE ENDOPEPTIDASES; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84961763025     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/1568026615666150915121447     Document Type: Review

References (174)

1. Rawlings, N.D.B., Alan J.; Bateman, A. MEROPS: the peptidase database. Nucl. Acids Res 2010, 38, D227-D233.
2. Craik, C.S.; Largman, C.; Fletcher, T.; Roczniak, S.; Barr, P.J.; Fletterick, R.; Rutter, W.J. Redesigning trypsin: alteration of substrate specificity. Science, 1985, 228, 291-297.
3. Craik, C.S.; Roczniak, S.; Sprang, S.; Fletterick, R.; Rutter, W. Redesigning trypsin via genetic engineering. J. Cell. Biochem., 1987, 33, 199-211.
4. Graf, L.; Boldogh, I.; Szilagyi, L.; Rutter, W.J. Redesigning the substrate specificity of trpsin: can trypsin be converted to a chymotrypsin-like protease? Protein Struct.-Funct., Proc. Int. Symp., 1990, 49-55.
5. Lai, L.-H.; Wang, Y.-L.; Xu, X.-J.; Tang, Y.-Q.; Ni, Y.-S.; Zhang, L.-X. Molecular design of trypsin towards high substrate selectivity. Sci. China, Series B: Chem., Life Sci., & Earth Sci., 1994, 37, 1-5.
6. Pinto, D.J.P.O., Michael, J.; Koch, S.; Rossi, K.A.; Alexander, R.S.; Smallwood, A.; Wong, P.C.; Rendina, A.R.; Luettgen, J.M.; Knabb, R.M.; He, K.; Xin, B.; Wexler, R.R.; Lam, P.Y.S. Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable nhibitor of blood coagulation factor Xa. J. Med. Chem., 2007, 50, 5339-5356.
7. Iwasaki, Y.K; Nishida, K.; Kato, T.; Nattel, S. Atrial fibrillation pathophysiology: implications for management. Circulation, 2011, 124, 2264-2277.
8. Fevig, J.M.; Buriak, J., Jr.; Cacciola, J.; Alexander, R.S.; Kettner, C.A.; Knabb, R.M.; Pruitt, J.R.; Weber, P.C.; Wexler, R.R. Rational design of boropeptide thrombin inhibitors: beta, beta-dialkylphenethylglycine P2 analogs of DuP 714 with greater selectivity over complement factor I and an improved safety profile. Bioorg. Med. Chem. Lett., 1998, 8, 301-306.
9. Fevig, J.M.; Cacciola, J.; Alexander, R.S.; Knabb, R.M.; Lam, G.N.; Wong, P.C.; Wexler, R.R. Preparation of meta-amidino-N,Ndisubstituted anilines as potent inhibitors of coagulation factor Xa. Bioorg. Med. Chem. Lett. 1998, 8, 3143-3148.
10. Fevig, J.M.; Pinto, D.J.; Han, Q.; Quan, M.L.; Pruitt, J.R.; Jacobson, I.C.; Galemmo, R.A., Jr.; Wang, S.; Orwat, M.J.; Bostrom, L.L.; Knabb, R.M.; Wong, P.C.; Lam, P.Y.S.; Wexler, R.R.: Synthesis and SAR of benzamidine factor Xa inhibitors containing a vicinally-substituted heterocyclic core. Bioorg. Med. Chem. Lett., 2001, 11, 641-645.
11. Han, Q.; Dominguez, C.; Stouten, P.F. W.; Park, J.M.; Duffy, D.E.; Galemmo, R.A., Jr.; Rossi, K.A.; Alexander, R.S.; Smallwood, A.M.; Wong, P.C.; Wright, M.M.; Leuttgen, J.M.; Knabb, R.M.; Wexler, R.R. Design, synthesis, and biological evaluation of potent and selective amidino bicyclic factor Xa inhibitors. J. Med. Chem., 2000, 43, 4398-445.
12. Pinto, D.J.P.; Orwat, M.J.; Wang, S.; Fevig, J.M.; Quan, M.L.; Amparo, E.; Cacciola, J.; Rossi, K.A.; Alexander, R.S.; Smallwood, A.M.; Luettgen, J.M.; Liang, L.; Aungst, B.J.; Wright, M.R.; Knabb, R.M.; Wong, P.C.; Wexler, R.R.; Lam, P.Y S. Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa. J. Med. Chem., 2001, 44, 566-578.
13. Quan, M.L.; Han, Q.; Fevig, J.M.; Lam, P.Y.S.; Bai, S.; Knabb, R.M.; Luettgen, J.M.; Wong, P.C.; Wexler, R.R. Bioorg. Med. Chem. Lett., 2006, 16, 1795-1798.
14. Qiao, J.X.; Chang, C.-H.; Cheney, D.L.; Morin, P.E.; Wang, G.Z.; King, S.R.; Wang, T.C.; Rendina, A.R.; Luettgen, J.M.; Knabb, R.M.; Wexler, R.R.; Lam, P.Y.S.: SAR and X-ray structures of enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and cyclohexyldiamine derivatives as inhibitors of coagulation Factor Xa. Bioorg. Med. Chem. Lett., 2007, 17, 4419-4427.
15. Qiao, J.X.; Wang, T.C.; Wang, G.Z.; Cheney, D.L.; He, K.; Rendina, A.R.; Xin, B.; Luettgen, J.M.; Knabb, R.M.; Wexler, R.R.; Lam, P.Y.S.: Enantiopure five-membered cyclicdiamine derivatives as potent and selective inhibitors of factor Xa. Improving in vitro metabolic stability via core modifications. Bioorg. Med. Chem. Lett., 2007, 17, 5041-5048.
16. Pinto, D.J.P.; Orwat, M.J.; Koch, S.; Rossi, K.A.; Alexander, R.S.; Smallwood, A.; Wong, P.C.; Rendina, A.R.; Luettgen, J.M.; Knabb, R.M.; He, K.; Xin, B.; Wexler, R.R.; Lam, P.Y.S. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J. Med. Chem., 2007, 50, 5339-5396.
17. Wong, P.C.; Watson, C.A.; Crain, E.J.: Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits. J. Thromb. Haemost., 2008, 6, 1736-1741.
18. Wong, P.C.; Crain, E.J.; Xin, B.; Wexler, R.R.; Lam, P.Y.S.; Pinto, D.J.; Luettgen, J.M.; Knabb, R.M. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J. Thromb. Haemost., 2008, 6, 820-829.
19. Corte, J.R.; Fang, T.; Pinto, D.J.P.; Han, W.; Hu, Z.; Jiang, X.-J.; Li, Y.-L.; Gauuan, J.F.; Hadden, M.; Orton, D.; Rendina, A.R.; Luettgen, J M.; Wong, P.C.; He, K.; Morin, P.E.; Chang, C.-H.; Cheney, D.L.; Knabb, R.M.; Wexler, R.R.; Lam, P.Y.S. Structureactivity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties. Bioorg. Med. Chem. Lett., 2008, 18, 2845-2849.
20. Wong, P.C.; Crain, E.J.; Watson, C.A.; Xin, B.: Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits. J. Thromb. Haemost., 2009, 7, 1313-1320.
21. Zhang, D.; He, K.; Raghavan, N.; Wang, L.; Mitroka, J.; Maxwell, B.D.; Knabb, R.M.; Frost, C.; Schuster, A.; Hao, F.; Gu, Z.; Humphreys, W.G.; Grossman, S. Comparative metabolism of 14Clabeled apixaban in mice, rats, rabbits, dogs, and humans. Drug Metab. Dispos., 2009, 37, 1738-1748.
22. Jiang, X.; Crain, E.J.; Luettgen, J.M.; Schumacher, W.A.; Wong, P.C. Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb. Haemost., 2009, 101, 780-782.
23. Galemmo, R.A., Jr.; Wells, B.L.; Rossi, K.A.; Alexander, R. S.; Dominguez, C.; Maduskuie, T.P.; Stouten, P.F.W.; Wright, M.R.; Aungst, B.J.; Wong, P.C.; Knabb, R.M.; Wexler, R.R. The de novo design and synthesis of cyclic urea inhibitors of factor Xa: optimization of the S4 ligand. Bioorg. Med. Chem. Lett., 2000, 10, 301-304.
24. Pruitt, J.R.; Pinto, D.J.; Estrella, M.J.; Bostrom, L.L.; Knabb, R.M.; Wong, P.C.; Wright, M.R.; Wexler, R.R.: Isoxazolines and isoxazoles as factor Xa inhibitors. Bioorg. Med. Chem. Lett., 2000, 10, 685-689.
25. Cacciola, J.; Fevig, J.M.; Stouten, P.F.W.; Alexander, R.S.; Knabb, R.M.; Wexler, R.R.: Synthesis and activity studies of conformationally restricted alpha-ketoamide factor Xa inhibitors. Bioorg. Med. Chem. Lett., 2000, 10, 1253-1256.
26. Quan, M.L.; Ellis, C.D.; He, M.Y.; Liauw, A.Y.; Woerner, F.J.; Alexander, R.S.; Knabb, R.M.; Lam, P.Y.S.; Luettgen, J.M.; Wong, P.C.; Wright, M.R.; Wexler, R.R. Nonbenzamidine tetrazole derivatives as factor Xa inhibitors. Bioorg. Med. Chem. Lett., 2003, 13, 369-373.
27. Quan, M.L.; Ellis, C.D.; He, M.Y.; Liauw, A.Y.; Lam, P.Y.S.; Rossi, K.A.; Knabb, R.M.; Luettgen, J.M.; Wright, M.R.; Wong, P.C.; Wexler, R.R. Nonbenzamidine isoxazoline derivatives as factor Xa inhibitors. Bioorg. Med. Chem. Lett., 2003, 13, 1023-1028.
28. Lam, P.Y.S.; Adams, J.J.; Clark, C.G.; Calhoun, W.J.; Luettgen, J.M.; Knabb, R.M.; Wexler, R.R.: Discovery of 3-amino-4-chlorophenyl P1 as a novel and potent benzamidine mimic via solid-phase synthesis of an isoxazoline library. Bioorg. Med. Chem. Lett., 2003, 13, 1795-1799.
29. Lam, P.Y.S.; Clark, C.G.; Li, R.; Pinto, D.J.P.; Orwat, M.J.; Galemmo, R.A.; Fevig, J.M.; Teleha, C.A.; Alexander, R.S.; Smallwood, A.M.; Rossi, K.A.; Wright, M.R.; Bai, S.A.; He, K.; Luettgen, J.M.; Wong, P.C.; Knabb, R.M.; Wexler, R.R. Structurebased design of novel guanidine/benzamidine mimics: potent and orally bioavailable factor Xa inhibitors as novel anticoagulants. J. Med. Chem., 2003, 46, 4405-4418.
30. Pruitt, J.R.; Pinto, D.J.P.; Galemmo, R.A., Jr.; Alexander, R.S.; Rossi, K.A.; Wells, B.L.; Drummond, S.; Bostrom, L.L.; Burdick, D.; Bruckner, R.; Chen, H.; Smallwood, A.; Wong, P.C.; Wright, M.R.; Bai, S.; Luettgen, J.M.; Knabb, R.M.; Lam, P.Y.S.; Wexler, R.R.: Discovery of 1-(2-aminomethylphenyl)-3-trifluoromethyl-N-[3-fluoro-2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl]-1H-pyrazole-5-carboxyamide (DPC602), a potent, selective, and orally bioavailable factor Xa inhibitor(1). J. Med. Chem., 2003, 46, 5298-5315.
31. Quan, M.L.; Lam, P.Y.S.; Han, Q.; Pinto, D.J.P.; He, M.Y.; Li, R.; Ellis, C.D.; Clark, C.G.; Teleha, C.A.; Sun, J.-H.; Alexander, R.S.; Bai, S.; Luettgen, J.M.; Knabb, R.M.; Wong, P.C.; Wexler, R.R.: Discovery of 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1Hpyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor. J. Med. Chem., 2005, 48, 1729-1744.
32. Shi, Y.; Zhang, J.; Stein, P.D.; Shi, M.; O'Connor, S.P.; Bisaha, S.N.; Li, C.; Atwal, K. S.; Bisacchi, G.S.; Sitkoff, D.; Pudzianowski, A.T.; Liu, E.C.; Hartl, K.S.; Seiler, S.M.; Youssef, S.; Steinbacher, T.E.; Schumacher, W.A.; Rendina, A.R.; Bozarth, J.M.; Peterson, T.L.; Zhang, G.; Zahler, R. Ketene aminal-based lactam derivatives as a novel class of orally active FXa inhibitors. Bioorg. Med. Chem. Lett., 2005, 15, 5453-5458.
33. Shi, Y.; Sitkoff, D.; Zhang, J.; Han, W.; Hu, Z.; Stein, P.D.; Wang, Y.; Kennedy, L. J.; O'Connor, S.P.; Ahmad, S.; Liu, E.C.K.; Seiler, S.M.; Lam, P.Y.S.; Robl, J.A.; Macor, J.E.; Atwal, K.S.; Zahler, R. Amino(methyl) pyrrolidines as novel scaffolds for factor Xa inhibitors. Bioorg. Med. Chem. Lett., 2007, 17, 5952-5958.
34. Ohta, T.; Satoshi, K; Yoshino, T.; Uoto, K.; Nakamoto, Y.; Naito, H.; Mochizuki, A.; Nagata, T.; Kanno, H.; Haginoya, N.; Yoshikawa, K.; Nagamochi, M.; Kobayashi, S.; Ono, M. Diamine Derivatives. WO Patent 2003000657A1; January 3, 2003.
35. Raskob, G.C., Alexander T.; Eriksson, B.I.; Puskas, D.; Shi, Minggao; Tomas, B; Weitz, J.I. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study. Thromb. Haemost., 2010, 104, 642-649.
36. Morishima, Y.; Shibano, T. Research and development strategy of antithrombotic agents: pharmacology of the oral factor Xa-inhibitor edoxaban. Nippon Yakurigaku Zasshi, 2010, 136, 83-87.
37. Ogata, K.; Mendell-Harary, J.; Tachibana, M.; Masumoto, H.; Oguma, T.; Kojima, M.; Kunitada, S.: Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J. Clin. Pharmacol., 2010, 50, 743-753.
38. Hara, T.; Yokoyama, A.; Tanabe, K.; Ishihara, H.; Iwamoto, M. DX-9065a, an orally active, specific inhibitor of factor Xa, inhibits thrombosis without affecting bleeding time in rats. Thromb. Haemost., 1995, 74, 635-639.
39. Hirayama, F.; Koshio, H.; Ishihara, T.; Watanuki, S.; Hachiya, S.; Kaizawa, H.; Kuramochi, T.; Katayama, N.; Kurihara, H.; Taniuchi, Y.; Sato, K.; Sakai-Moritani, Y.; Kaku, S.; Kawasaki, T.; Matsumoto, Y.; Sakamoto, S.; Tsukamoto, S.-I.: Design, synthesis and biological activity of YM-60828 derivatives: potent and orallybioavailable factor Xa inhibitors based on naphthoanilide and naphthalensulfonanilide templates. Bioorg. Med. Chem. Lett., 2002, 10, 2597-2610.
40. Hirayama, F.; Koshio, H.; Katayama, N.; Ishihara, T.; Kaizawa, H.; Taniuchi, Y.; Sato, K.; Sakai-Moritani, Y.; Kaku, S.; Kurihara, H.; Kawasaki, T.; Matsumoto, Y.; Sakamoto, S.; Tsukamoto, S.-I. Design, synthesis and biological activity of YM-60828 derivatives. Part 2: potent and orally-bioavailable factor Xa inhibitors based on benzothiadiazine-4-one template. Bioorg. Med. Chem. Lett., 2003, 11, 367-381.
41. Nagata, T.; Yoshino, T.; Haginoya, N.; Yoshikawa, K.; Isobe, Y.; Furugohri, T.; Kanno, H. Cycloalkanediamine derivatives as novel blood coagulation factor Xa inhibitors. Bioorg. Med. Chem. Lett., 2007, 17, 4683-4688.
42. Nagata, T.; Yoshino, T.; Haginoya, N.; Yoshikawa, K.; Nagamochi, M.; Kobayashi, S.; Komoriya, S.; Yokomizo, A.; Muto, R.; Yamaguchi, M.; Osanai, K.; Suzuki, M.; Kanno, H. Abstracts of Papers, 234th ACS National Meeting, Boston, MA, United States, August 19-23, 2007, MEDI.
43. Nagata, T.; Nagamochi, M.; Kobayashi, S.; Komoriya, S.; Yoshino, T.; Kanno, H.: Stereoselective synthesis and biological evaluation of 3,4-diaminocyclohexanecarboxylic acid derivatives as factor Xa inhibitors. Bioorg. Med. Chem. Lett., 2008, 18, 4587-4592.
44. Mochizuki, A.; Nakamoto, Y.; Naito, H.; Uoto, K.; Ohta, T. Design, synthesis, and biological activity of piperidine diamine derivatives as factor Xa inhibitor. Bioorg. Med. Chem. Lett., 2008, 18, 782-787.
45. Mochizuki, A.; Nagata, T.; Kanno, H. Novel diamide derivative. W.O. Patent 2008123017A1; October 16, 2008.
46. Mochizuki, A.; Nagata, T.; Takano, D.; Kanno, H. Novel diamide derivative. W.O. Patent 2008111299A1; September 18, 2008.
47. Nagata, T.; Yoshino, T.; Haginoya, N.; Yoshikawa, K.; Nagamochi, M.; Kobayashi, S.; Komoriya, S.; Yokomizo, A.; Muto, R.; Yamaguchi, M.; Osanai, K.; Suzuki, M.; Kanno, H. Discovery of N-[(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(dimethylcarbamoyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride: a novel, potent and orally active direct inhibitor of factor Xa. Bioorg. Med. Chem., 2009, 17, 1193-1206.
48. Yoshikawa, K.; Kobayashi, S.; Nakamoto, Y.; Haginoya, N.; Komoriya, S.; Yoshino, T.; Nagata, T.; Mochizuki, A.; Watanabe, K.; Suzuki, M.; Kanno, H.; Ohta, T. Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part II: exploration of 6-6 fused rings as alternative S1 moieties. Bioorg. Med. Chem., 2009, 17, 8221-8233.
49. Yoshikawa, K.; Yokomizo, A.; Naito, H.; Haginoya, N.; Kobayashi, S.; Yoshino, T.; Nagata, T.; Mochizuki, A.; Osanai, K.; Watanabe, K.; Kanno, H.; Ohta, T. Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part I: exploration of 5-6 fused rings as alternative S1 moieties. Bioorg. Med. Chem., 2009, 17, 8206-8220.
50. Weitz, J.I.C., Stuart J.; Patel, I.; Salazar, D.; Rohatagi, S.; Mendell, J.; Kastrissios, H.; Jin, J.; Kunitada, S. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb. Haemost., 2010, 104, 633-641.
51. Koshio, H.; Hirayama, F.; Ishihara, T.; Kaizawa, H.; Shigenaga, T.; Taniuchi, Y.; Sato, K.; Moritani, Y.; Iwatsuki, Y.; Uemura, T.; Kaku, S.; Kawasaki, T.; Matsumoto, Y.; Sakamoto, S.; Tsukamoto, S.-I.: Orally active factor Xa inhibitor: synthesis and biological activity of masked amidines as prodrugs of novel 1,4-diazepane derivatives. Bioorg. Med. Chem., 2004, 12, 5415-5426.
52. Koshio, H.; Hirayama, F.; Ishihara, T.; Taniuchi, Y.; Sato, K.; Sakai-Moritani, Y.; Kaku, S.; Kawasaki, T.; Matsumoto, Y.; Sakamoto, S.; Tsukamoto, S.-I.: Synthesis and biological activity of novel 1,4-diazepane derivatives as factor Xa inhibitor with potent anticoagulant and antithrombotic activity. Bioorg. Med. Chem., 2004, 12, 2179-2191.
53. Koshio, H.; Hirayama, F.; Ishihara, T.; Shiraki, R.; Shigenaga, T.; Taniuchi, Y.; Sato, K.; Moritani, Y.; Iwatsuki, Y.; Kaku, S.; Katayama, N.; Kawasaki, T.; Matsumoto, Y.; Sakamoto, S.; Tsukamoto, S.-I.: Synthesis and biological activity of novel 1,2-disubstituted benzene derivatives as factor Xa inhibitors. Bioorg. Med. Chem., 2005, 13, 1305-1323.
54. Kubitza, D.; Becka, M.; Mueck, W.; Zuehlsdorf, M.: Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban--an oral, direct factor Xa inhibitor--are not affected by aspirin. J. Clin. Pharmacol., 2006, 46, 981-990.
55. Kubitza, D.; Haas, S. Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases. Expert Opin Investig Drugs 2006, 15, 843-855.
56. Kubitza, D.; Becka, M.; Zuehlsdorf, M.; Mueck, W.: Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J. Clin. Pharmacol., 2006, 46, 549-558.
57. Perzborn, E.; Kubitza, D.; Misselwitz, F.: Rivaroxaban. A novel, oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Haemostaseologie Stuttgart, Germany, 2007, 27, 282-289.
58. Laux, V.; Perzborn, E.; Kubitza, D.; Misselwitz, F. Preclinical and clinical characteristics of rivaroxaban: a novel, oral, direct factor Xa inhibitor. Semin. Thromb. Hemost., 2007, 33, 515-523.
59. Mueck, W.; Becka, M.; Kubitza, D.; Voith, B.; Zuehlsdorf, M. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor xa inhibitor--in healthy subjects. International J. Clin. Pharmacol. Ther., 2007, 45, 335-344.
60. Kubitza, D.; Becka, M.; Mueck, W.; Zuehlsdorf, M. Rivaroxaban (BAY 59-7939)--an oral, direct Factor Xa inhibitor--has no clinically relevant interaction with naproxen. Br. J. Clin. Pharmacol., 2007, 63, 469-476.
61. Kubitza, D.; Becka, M.; Zuehlsdorf, M.; Mueck, W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J. Clin. Pharmacol., 2007, 47, 218-226.
62. Kubitza, D.; Becka, M.; Roth, A.; Mueck, W.: Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr. Med. Res. Opin., 2008, 24, 2757-2765.
63. Kubitza, D.; Becka, M.; Mueck, W.; Zuehlsdorf, M.: Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban--an oral, direct factor Xa inhibitor--are not affected by aspirin. J. Clin. Pharmacol. 2008, 46, 981-990.
64. Mueck, W.; Borris, L.C.; Dahl, O.E.; Haas, S.; Huisman, M.V.; Kakkar, A.K.; Kaelebo, P.; Muelhofer, E.; Misselwitz, F.; Eriksson, B.I.: Population pharmacokinetics and pharmacodynamics of onceand twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb. Haemost., 2008, 100, 453-461.
65. Rohde, G. Determination of rivaroxaban--a novel, oral, direct Factor Xa inhibitor--in human plasma by high-performance liquid chromatography-tandem mass spectrometry. J. Chromatogr. B: Analyt. Tech. Biomed. Life Sci., 2008, 872, 43-50.
66. Mueck, W.; Eriksson, B.I.; Bauer, K.A.; Borris, L.; Dahl, O.E.; Fisher, W.D.; Gent, M.; Haas, S.; Huisman, M.V.; Kakkar, A.K.; Kaelebo, P.; Kwong, L.M.; Misselwitz, F.; Turpie, A.G.G.: Population pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor Xa inhibitor--in patients undergoing major orthopaedic surgery. Clin. Pharmacokinet., 2008, 47, 203-216.
67. Kubitza, D.; Mueck, W.; Becka, M. Randomized, double-blind, crossover study to investigate the effect of rivaroxaban on QTinterval prolongation. Drug Saf., 2008, 31, 67-77.
68. Laux, V.; Perzborn, E.; Heitmeier, S.; von Degenfeld, G.; Dittrich-Wengenroth, E.; Buchmueller, A.; Gerdes, C.; Misselwitz, F. Direct inhibitors of coagulation proteins-the end of the heparin and low-molecular-weight heparin era for anticoagulant therapy? Thromb. Haemost., 2009, 102, 892-899.
69. Weinz, C.; Schwarz, T.; Kubitza, D.; Mueck, W.; Lang, D. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab. Dispos., 2009, 37, 1056-1064.
70. Lang, D.; Freudenberger, C.; Weinz, C. In vitro metabolism of rivaroxaban, an oral, direct factor Xa inhibitor, in liver microsomes and hepatocytes of rats, dogs, and humans. Drug Metab. Dispos., 2009, 37, 1046-1055.
71. Zhao, X.; Sun, P.; Zhou, Y.; Liu, Y.; Zhang, H.; Mueck, W.; Kubitza, D.; Bauer R.J.; Zhang, H.; Cui, Y. Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects. Br. J. Clin. Pharmacol., 2009, 68, 77-88.
72. Perzborn, E. Factor Xa inhibitors--new anticoagulants for secondary haemostasis. Hamostaseologie, 2009, 29, 260-267.
73. Roehrig, S.; Straub, A.; Pohlmann, J.; Lampe, T.; Pernerstorfer, J.; Schlemmer, K.-H.; Reinemer, P.; Perzborn, E. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J. Med. Chem., 2005, 48, 5900-5908.
74. Roehrig, S.; Straub, A.; Pohlmann, J.; Lampe, T.; Pernerstorfer, J.; Schlemmer, K. H.; Perzborn, E. Abstracts of Papers, 228th ACS National Meeting, Philadelphia, PA, United States, August 22-26, 2004, MEDI.
75. Guertin, K. R.; Choi, Y.-M. The discovery of the Factor Xa inhibitor otamixaban: from lead identification to clinical development. Curr. Med. Chem., 2007, 14, 2471-2481.
76. Klein, S.I.; Czekaj, M.; Gardner, C.J.; Guertin, K.R.; Cheney, D.L.; Spada, A.P.; Bolton, S.A.; Brown, K.; Colussi, D.; Heran, C.L.; Morgan, S.R.; Leadley, R.J.; Dunwiddie, C.T.; Perrone, M.H.; Chu, V.: Identification and initial structure-activity relationships of a novel class of nonpeptide inhibitors of blood coagulation factor Xa. J. Med. Chem., 1998, 41, 437-450.
77. Hinder, M.; Paccaly, A.; Frick, A.; Shukla, U.; Simcox, K.; Miller, B.; Gebauer, A.: Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, with tirofiban in healthy volunteers. Thromb. Haemost., 2005, 93, 794-795.
78. Hinder, M.; Frick, A.; Jordaan, P.; Hesse, G.; Gebauer, A.; Maas, J.; Paccaly, A. Direct and rapid inhibition of factor Xa by otamixaban: a pharmacokinetic and pharmacodynamic investigation in patients with coronary artery disease. Clin Pharm Ther (New York, NY, United States), 2006, 80, 691-702.
79. Hinder, M.; Frick, A.; Rosenburg, R.; Hesse, G.; Ozoux, M.-L.; Laux, V.; Scholtz, H.; Gebauer, A.; Paccaly, A. Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid. Thromb. Haemost., 2006, 95, 224-228.
80. Paccaly, A.; Frick, A.; Ozoux, M.-L.; Chu, V.; Rosenburg, R.; Hinder, M.; Shukla, U.; Jensen, B.K. Pharmacokinetic/ pharmacodynamic relationships for otamixaban, a direct factor Xa inhibitor, in healthy subjects. J. Clin. Pharmacol., 2006, 46, 45-51.
81. Paccaly, A.; Frick, A.; Rohatagi, S.; Liu, J.; Shukla, U.; Rosenburg, R.; Hinder, M.; Jensen, B.K. Pharmacokinetics of otamixaban, a direct factor Xa inhibitor, in healthy male subjects: pharmacokinetic model development for phase 2/3 simulation of exposure. J. Clin. Pharmacol., 2006, 46, 37-44.
82. Ebner, T.; Wagner, K.; Wienen, W. Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab. Dispos., 2010, 38, 1567-1575.
83. Eisert, W.G.; Hauel, N.; Stangier, J.; Wienen, W.; Clemens, A.; van Ryn, J. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler. Thromb. Vas. Biol., 2010, 30, 1885-1889.
84. Stangier, J.; Clemens, A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin. Appl. Thromb. Hemost., 2009, 15, 9S-16S.
85. Banner, D. W.; Hadvary, P. Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active sitedirected inhibitors. J. Biol. Chem., 1991, 266, 20085-20093.
86. Brandstetter, H.; Turk, D.; Hoeffken, H.W.; Grosse, D.; Stuerzebecher, J.; Martin, P.D.; Edwards, B.F.P.; Bode, W. Refined 2.3 A X-ray crystal structure of bovine thrombin complexes formed with the benzamidine and arginine-based thrombin inhibitors NAPAP, 4-TAPAP and MQPA. A starting point for improving antithrombotics. J. Mol. Biol., 1992, 226, 1085-1099.
87. Hauel, N.H.; Nar, H.; Priepke, H.; Ries, U.; Stassen, J.-M.; Wienen, W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J. Med. Chem., 2002, 45, 1757-1766.
88. Stangier, J.; Eriksson, B.I.; Dahl, O.E.; Ahnfelt, L.; Nehmiz, G.; Staehle, H.; Rathgen, K.; Svaerd, R. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J. Clin. Pharmacol., 2005, 45, 555-563.
89. Liesenfeld, K.-H.; Schaefer, H.G.; Troconiz, I.F.; Tillmann, C.; Eriksson, B.I.; Stangier, J. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br. J. Clin. Pharmacol., 2006, 62, 527-537.
90. Wienen, W.; Stassen, J.M.; Priepke, H.; Ries, U.J.; Hauel, N. Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis. J. Thromb. Haemost., 2007, 5, 1237-1242.
91. Wienen, W.; Stassen, J.-M.; Priepke, H.; Ries, U.J.; Hauel, N. Invitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb. Haemost., 2007, 98, 155-162.
92. Wienen, W.; Stassen, J.-M.; Priepke, H.; Ries, U.J.; Hauel, N. Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats. Thromb. Haemost., 2007, 98, 333-338.
93. Stangier, J.; Rathgen, K.; Staehle, H.; Gansser, D.; Roth, W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br. J. Clin. Pharmacol., 2007, 64, 292-303.
94. Blech, S.; Ebner, T.; Ludwig-Schwellinger, E.; Stangier, J.; Roth, W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab. Disp., 2008, 36, 386-399.
95. Stangier, J.; Staehle, H.; Rathgen, K.; Fuhr, R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin. Pharmacokinet., 2008, 47, 47-59.
96. Stangier, J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin. Pharmacokinet., 2008, 47, 285-295.
97. Stangier, J.; Staehle, H.; Rathgen, K.; Roth, W.; Shakeri-Nejad, K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J. Clin. Pharmacol., 2008, 48, 1411-1419.
98. Stangier, J.; Rathgen, K.; Staehle, H.; Reseski, K.; Koernicke, T.; Roth, W. Coadministration of dabigatran etexilate and atorvastatin: assessment of potential impact on pharmacokinetics and pharmacodynamics. Am. J. Cardiovasc. Drugs, 2009, 9, 59-68.
99. Bajusz, S.; Barabas, E.; Fauszt, I.; Feher, A.; Horvath, G.; Juhasz, A.; Szabo, A. G.; Szell, E. Active site-directed thrombin inhibitors: alpha-hydroxyacyl-prolyl-arginals. New orally active stable analogs of D-Phe-Pro-Arg-H. Bioorg. Med. Chem., 1995, 3, 1079-1089.
100. Klein, S.I.; Dener, J.M.; Molino, B.F.; Gardner, C.J.; D'Alisa, R.; Dunwiddie, C.T.; Kasiewski, C.; Leadley, R.J. O-benzyl hydroxyproline as a bioisostere for Phe-Pro: Novel dipeptide thrombin inhibitors. Bioorg. Med. Chem. Lett., 1996, 6, 2225-2230.
101. Wiley, M.R.; Chirgadze, N.Y.; Clawson, D.K.; Craft, T.J.; Gifford-Moore, D.S.; Jones, N.D.; Olkowaki, J.L.; Schacht, A.L.; Weir, L.C.; Smith, G.F.: Serine protease selectivity of the thrombin inhibitor D-Phe-Pro-Agmatine and its homologs. Bioorg. Med. Chem. Lett., 1995, 5, 2835-2840.
102. Wiley, M.R.; Chirgadze, N.Y.; Clawson, D.K.; Craft, T.J.; Gifford-Moore, D.S.; Jones, N.D.; Olkowski, J.L.; Weir, L.C.; Smith, G.F. D-Phe-Pro-p-Amidinobenzylamine: A potent and highly selective thrombin inhibitor. Bioorg. Med. Chem. Lett., 1996, 6, 2387-2392.
103. Feng, D.-M.; Gardell, S.J.; Lewis, S.D.; Bock, M.G.; Chen, Z.; Freidinger, R.M.; Naylor-Olsen, A.; Ramjit, H.G.; Woltmann, R.; Baskin, E.P.; Lynch, J.J.; Lucas, R.; Shafer, J.A.; Dancheck, K.B.; Chen, I.W.; Mao, S.-S.; Krueger, J.A.; Hare, T.R.; Mulichak, A.M.; Vacca, J.P.: Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position. J. Med. Chem., 1997, 40, 3726-3733.
104. Lumma, W.C., Jr.; Witherup, K.M.; Tucker, T.J.; Brady, S.F.; Sisko, J.T.; Naylor-Olsen, A.M.; Lewis, S.D.; Lucas, B.J.; Vacca, J.P. Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1 substructures: rapid structure-activity studies by solid-phase synthesis. J. Med. Chem., 1998, 41, 1011-1013.
105. Tucker, T.J.; Brady, S.F.; Lumma, W.C.; Lewis, S.D.; Gardell, S.J.; Naylor-Olsen, A.M.; Yan, Y.; Sisko, J.T.; Stauffer, K.J.; Lucas, B.J.; Lynch, J.J.; Cook, J.J.; Stranieri, M.T.; Holahan, M.A.; Lyle, E.A.; Baskin, E.P.; Chen, I.W.; Dancheck, K.B.; Krueger, J.A.; Cooper, C.M.; Vacca, J.P. Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position. J. Med. Chem., 1998, 41, 3210-3219.
106. Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; He, W.; Condon, S.M.; Davis, R.S.; Hanney, B.A.; Spada, A.P.; Burns, C.J.; Jiang, J.Z.; Li, A.; Myers, M.R.; Lau, W.F.; Poli, G.B. Substituted Oxoaxaheterocyclyl Factor Xa Inhibitors. W.O. Patent 1999037304 A1; July 29, 1999.
107. Stuerzebecher, J.; Prasa, D.; Hauptmann, J.; Vieweg, H.; Wikstroem, P. Synthesis and structure-activity relationships of potent thrombin inhibitors: piperazides of 3-amidinophenylalanine. J. Med. Chem., 1997, 40, 3091-3099.
108. Young, W.B.; Kolesnikov, A.; Rai, R.; Sprengeler, P.A.; Leahy, E.M.; Shrader, W.D.; Sangalang, J.; Burgess-Henry, J.; Spencer, J.; Elrod, K.; Cregar, L. Optimization of a screening lead for factor VIIa/TF. Bioorg. Med. Chem. Lett., 2001, 11, 2253-2256.
109. Hanessian, S.; Therrien, E.; Granberg, K.; Nilsson, I. Targeting thrombin and factor VIIa: design, synthesis, and inhibitory activity of functionally relevant indolizidinones. Bioorg. Med. Chem. Lett., 2002, 12, 2907-2911.
110. Parlow, J.J.; Case, B.L.; Dice, T.A.; Fenton, R.L.; Hayes, M.J.; Jones, D.E.; Neumann, W.L.; Wood, R.S.; Lachance, R.M.; Girard, T.J.; Nicholson, N.S.; Clare, M.; Stegeman, R.A.; Stevens, A.M.; Stallings, W.C.; Kurumbail, R.G.; South, M.S.: Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex. J. Med. Chem., 2003, 46, 4050-4062.
111. Parlow, J.J.; Dice, T.A.; Lachance, R.M.; Girard, T.J.; Stevens, A.M.; Stegeman, R.A.; Stallings, W.C.; Kurumbail, R.G.; South, M.S.: Polymer-assisted solution-phase library synthesis and crystal structure of alpha-ketothiazoles as tissue factor VIIa inhibitors. J. Med. Chem., 2003, 46, 4043-4049.
112. Parlow, J.J.; Kurumbail, R.G.; Stegeman, R.A.; Stevens, A.M.; Stallings, W.C.; South, M.S. Synthesis and X-ray crystal structures of substituted fluorobenzene and benzoquinone inhibitors of the tissue factor VIIa complex. Bioorg. Med. Chem. Lett., 2003, 13, 3721-3725.
113. Parlow, J.J.; Kurumbail, R.G.; Stegeman, R.A.; Stevens, A.M.; Stallings, W.C.; South, M.S. Design, synthesis, and crystal structure of selective 2-pyridone tissue factor VIIa inhibitors. J. Med. Chem., 2003, 46, 4696-4701.
114. Parlow, J.J.; Stevens, A.M.; Stegeman, R.A.; Stallings, W.C.; Kurumbail, R.G.; South, M.S. Synthesis and crystal structures of substituted benzenes and benzoquinones as tissue factor VIIa inhibitors. J. Med. Chem., 2003, 46, 4297-4312.
115. South, M.S.; Case, B.L.; Wood, R.S.; Jones, D.E.; Hayes, M.J.; Girard, T.J.; Lachance, R.M.; Nicholson, N.S.; Clare, M.; Stevens, A.M.; Stegeman, R.A.; Stallings, W.C.; Kurumbail, R.G.; Parlow, J.J. Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex. Bioorg. Med. Chem. Lett., 2003, 13, 2319-2325.
116. South, M.S.; Dice, T.A.; Girard, T.J.; Lachance, R.M.; Stevens, A.M.; Stegeman, R.A.; Stallings, W.C.; Kurumbail, R.G.; Parlow, J.J. Polymer-assisted solution-phase (PASP) parallel synthesis of an alpha-ketothiazole library as tissue factor VIIa inhibitors. Bioorg. Med. Chem. Lett., 2003, 13, 2363-2367.
117. Klingler, O.; Matter, H.; Schudok, M.; Donghi, M.; Czech, J.; Lorenz, M.; Nestler, H.P.; Szillat, H.; Schreuder, H. Structurebased design of amidinophenylurea-derivatives for factor VIIa inhibition. Bioorg. Med. Chem. Lett., 2004, 14, 3715-3720.
118. Zbinden, G.K.; Banner, D.W.; Ackermann, J.; D'Arcy, A.; Kirchhofer, D.; Ji, Y.-H.; Tschopp, T.B.; Wallbaum, S.; Weber, L. Design of selective phenylglycine amide tissue factor/factor VIIa inhibitors. Bioorg. Med. Chem. Lett., 2005, 15, 817-822.
119. Zbinden, K.G.; Obst-Sander, U.; Hilpert, K.; Kuehne, H.; Banner, D.W.; Boehm, H.-J.; Stahl, M.; Ackermann, J.; Alig, L.; Weber, L.; Wessel, H.P.; Riederer, M.A.; Tschopp, T.B.; Lave, T.: Selective and orally bioavailable phenylglycine tissue factor/factor VIIa inhibitors. Bioorg. Med. Chem. Lett., 2005, 15, 5344-5352.
120. Zbinden, K.G.; Banner, D.W.; Hilpert, K.; Himber, J.; Lave, T.; Riederer, M. A.; Stahl, M.; Tschopp, T.B.; Obst-Sander, U. Dosedependent antithrombotic activity of an orally active tissue factor/ factor VIIa inhibitor without concomitant enhancement of bleeding propensity. Bioorg. Med. Chem. Lett., 2006, 14, 5357-5369.
121. Sagi, K.; Fujita, K.; Sugiki, M.; Takahashi, M.; Takehana, S.; Tashiro, K.; Kayahara, T.; Yamanashi, M.; Fukuda, Y.; Oono, S.; Okajima, A.; Iwata, S.; Shoji, M.; Sakurai, K. Optimization of a coagulation factor VIIa inhibitor found in factor Xa inhibitor library. Bioorg. Med. Chem. Lett., 2005, 13, 1487-1496.
122. Buckman, B.O.; Chou, Y.-L.; McCarrick, M.; Liang, A.; Lentz, D.; Mohan, R.; Morrissey, M. M.; Shaw, K.J.; Trinh, L.; Light, D.R. Solid-phase synthesis of naphthylamidines as factor VIIa/tissue factor inhibitors. Bioorg. Med. Chem. Lett., 2005, 15, 2249-2252.
123. Kohrt, J.T.; Filipski, K.J.; Cody, W.L.; Cai, C.; Dudley, D.A.; Van Huis, C.A.; Willardsen, J.A.; Rapundalo, S.T.; Saiya-Cork, K.; Leadley, R. J.; Narasimhan, L.; Zhang, E.; Whitlow, M.; Adler, M.; McLean, K.; Chou, Y.-L.; McKnight, C.; Arnaiz, D.O.; Shaw, K.J.; Light, D.R.; Edmunds, J.J. The discovery of fluoropyridine-based inhibitors of the Factor VIIa/TF complex. Bioorg. Med. Chem. Lett., 2005, 15, 4752-4756.
124. Hu, H.; Kolesnikov, A.; Riggs, J.R.; Wesson, K.E.; Stephens, R.; Leahy, E.M.; Shrader, W.D.; Sprengeler, P.A.; Green, M.J.; Sanford, E.; Nguyen, M.; Gjerstad, E.; Cabuslay, R.; Young, W. B. Potent 4-amino-5-azaindole factor VIIa inhibitors. Bioorg. Med. Chem. Lett., 2006, 16, 4567-4570.
125. Shrader, W.D.; Kolesnikov, A.; Burgess-Henry, J.; Rai, R.; Hendrix, J.; Hu, H.; Torkelson, S.; Ton, T.; Young, W.B.; Katz, B.A.; Yu, C.; Tang, J.; Cabuslay, R.; Sanford, E.; Janc, J. W.; Sprengeler, P.A. Factor VIIa inhibitors: gaining selectivity within the trypsin family. Bioorg. Med. Chem. Lett., 2006, 16, 1596-1600.
126. Kolesnikov, A.; Rai, R.; Young, W.B.; Mordenti, J.; Liu, L.; Torkelson, S.; Shrader, W.D.; Leahy, E.M.; Hu, H.; Gjerstad, E.; Janc, J.; Katz, B.A.; Sprengeler, P.A. Factor VIIa inhibitors: improved pharmacokinetic parameters. Bioorg. Med. Chem. Lett., 2006, 16, 2243-2246.
127. Young, W.B.; Mordenti, J.; Torkelson, S.; Shrader, W.D.; Kolesnikov, A.; Rai, R.; Liu, L.; Hu, H.; Leahy, E.M.; Green, M.J.; Sprengeler, P.A.; Katz, B.A.; Yu, C.; Janc, J.W.; Elrod, K.C.; Marzec, U.M.; Hanson, S. R. Factor VIIa inhibitors: chemical optimization, preclinical pharmacokinetics, pharmacodynamics, and efficacy in an arterial baboon thrombosis model. Bioorg. Med. Chem. Lett., 2006, 16, 2037-2041.
128. Riggs, J.R.; Hu, H.; Kolesnikov, A.; Leahy, E.M.; Wesson, K.E.; Shrader, W.D.; Vijaykumar, D.; Wahl, T. A.; Tong, Z.; Sprengeler, P.A.; Green, M.J.; Yu, C.; Katz, B.A.; Sanford, E.; Nguyen, M.; Cabuslay, R.; Young, W.B. Novel 5-azaindole factor VIIa inhibitors. Bioorg. Med. Chem. Lett., 2006, 16, 3197-3200.
129. Rai, R.; Kolesnikov, A.; Sprengeler, P.A.; Torkelson, S.; Ton, T.; Katz, B.A.; Yu, C.; Hendrix, J.; Shrader, W.D.; Stephens, R.; Cabuslay, R.; Sanford, E.; Young, W.B. Discovery of novel heterocyclic factor VIIa inhibitors. Bioorg. Med. Chem. Lett., 2006, 16, 2270-2273.
130. Vijaykumar, D.; Rai, R.; Shaghafi, M.; Ton, T.; Torkelson, S.; Leahy, E.M.; Riggs, J.R.; Hu, H.; Sprengeler, P.A.; Shrader, W.D.; O'Bryan, C.; Cabuslay, R.; Sanford, E.; Gjerstadt, E.; Liu, L.; Sukbuntherng, J.; Young, W. B. Bioorg. Med. Chem. Lett., 2006, 16, 3829-3832.
131. Riggs, J.R.; Kolesnikov, A.; Hendrix, J.; Young, W.B.; Shrader, W.D.; Vijaykumar, D.; Stephens, R.; Liu, L.; Pan, L.; Mordenti, J.; Green, M.J.; Sukbuntherng, J. Factor VIIa inhibitors: a prodrug strategy to improve oral bioavailability. Bioorg. Med. Chem. Lett., 2006, 16, 2224-2228.
132. Miller, J.S.; Westin, E.H.; Schwartz, L.B.: Cloning and characterization of complementary DNA for human tryptase. J. Clin. Invest., 1989, 84, 1188-1195.
133. Pallaoro, M.; Fejzo, M.S.; Shayesteh, L.; Blount, J.L.; Caughey, G.H.: Characterization of genes encoding known and novel human mast cell tryptases on chromosome 16p13.3. J. Biol. Chem., 1999, 274, 3355-3362.
134. Cairns, J.A.; Walls, A.F. Mast cell tryptase is a mitogen for epithelial cells. Stimulation of IL-8 production and intercellular adhesion molecule-1 expression. J. Immunol., 1996, 156, 275-285.
135. Cairns, J.A.; Walls, A.F. Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. J. Clin. Invest., 1997, 99, 1313-1321.
136. Cairns, J.A.: Inhibitors of mast cell tryptase beta as therapeutics for the treatment of asthma and inflammatory disorders. Pulm. Pharmacol. Ther., 2005, 18, 55-66.
137. Schwartz, L.B.; Sakai, K.; Bradford, T.R.; Ren, S.; Zweiman, B.; Worobec, A..; Metcalfe, D.D. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J. Clin. Invest., 1995, 96, 2702-2710.
138. Sakai, K.; Ren, S.; Schwartz, L.B. A novel heparin-dependent processing pathway for human tryptase. Autocatalysis followed by activation with dipeptidyl peptidase I. J. Clin. Invest., 1996, 97, 988-95.
139. Schwartz, L.B.; Bradford, T.R.; Littman, B.H.; Wintroub, B.U. The fibrinogenolytic activity of purified tryptase from human lung mast cells. J. Immunol., 1985, 135, 2762-2767.
140. Caughey, G.H. Of mites and men: trypsin-like proteases in the lungs. Am. J. Respir. Cell Mol. Biol., 1997, 16, 621-628.
141. Johnson, P.R.; Ammit, A.J.; Carlin, S.M.; Armour, C.L.; Caughey, G.H.; Black, J.L. Mast cell tryptase potentiates histamine-induced contraction in human sensitized bronchus. Eur. Respir. J., 1997, 10, 38-43.
142. Rice, K.D.; Tanaka, R.D.; Katz, B.A.; Numerof, R.P.; Moore, W.R. Inhibitors of tryptase for the treatment of mast cell-mediated diseases. Curr. Pharm. Des., 1998, 4, 381-396.
143. De Sanctis, G.T.; Merchant, M.; Beier, D.R.; Dredge, R.D.; Grobholz, J.K.; Martin, T.R.; Lander, E.S.; Drazen, J.M. Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice. Nature Genetics 1995, 11, 150-154.
144. Ono, S.; Kuwahara, S.; Takeuchi, M.; Sakashita, H.; Naito, Y.; Kondo, T.: Syntheses and evaluation of amidinobenzofuran derivatives as tryptase inhibitors. Bioorg. Med. Chem. Lett., 1999, 9, 3285-3290.
145. Rice, K.D.; Gangloff, A.R.; Kuo, E.Y.L.; Dener, J.M.; Wang, V.R.; Lum, R.; Newcomb, W.S.; Havel, C.; Putnam, D.; Cregar, L.; Wong, M.; Warne, R.L.: Syntheses and evaluation of amidinobenzofuran derivatives as tryptase inhibitors. Bioorg. Med. Chem. Lett., 2000, 10, 2357-60.
146. Rice, K.D.; Wang, V.R.; Gangloff, A.R.; Kuo, E.Y.L.; Dener, J.M.; Newcomb, W.S.; Young, W.B.; Putnam, D.; Cregar, L.; Wong, M.; Simpson, P.J. Dibasic inhibitors of human mast cell tryptase. Part 2: structure-activity relationships and requirements for potent activity. Bioorg. Med. Chem. Lett., 2000, 10, 2361-2366.
147. Rice, K.D.; Tanaka, R.D.; Katz, B.A.; Numerof, R.P.; Moore, W.R. Inhibitors of tryptase for the treatment of mast cell-mediated diseases. Curr. Pharm. Des., 1998, 4, 381-396.
148. Rice, K.D.; Moore, W.R. In: High Throughput Screening for Novel Anti-Inflammatories, Michael Khan, Ed.; Birkhauser Verlag: Basel, 2000, pp. 101-102.
149. Gangloff, A.R.: Tryptase inhibitors in the treatment of pulmonary diseases. Curr. Opin. Investig. Drugs, 2000, 1, 79-85.
150. Peter J. Barnes, London T. Bolliger, Clark, J.M.; Van Dyke, R.E.; Kurth, M.C. In: Progress in Respiratory Research; Trevor T. Hansel, Ed.; Karger: London, 2001; 31, pp. 170-173.
151. Dener, J.M.; Rice, K.D.; Newcomb, W.S.; Wang, V.R.; Young, W.B.; Gangloff, A.R.; Kuo, E.Y.L.; Cregar, L.; Putnam, D.; Wong, M. Dibasic inhibitors of human mast cell tryptase. Part 3: identification of a series of potent and selective inhibitors containing the benzamidine functionality. Bioorg. Med. Chem. Lett., 2001, 11, 1629-1633.
152. Dener, J.M.; Wang, V.R.; Rice, K.D.; Gangloff, A.R.; Kuo, E.Y.L.; Newcomb, W.S.; Putnam, D.; Wong, M.: Monocharged inhibitors of mast cell tryptase derived from potent and selective dibasic inhibitors. Bioorg. Med. Chem. Lett., 2001, 11, 2325-2350.
153. Tremaine, W.J.; Brzezinski, A.; Katz, J.A.; Wolf, D.C.; Fleming, T.J.; Mordenti, J.; Strenkoski-Nix, L.C.; Kurth, AXYS Ulcerative Colitis Study Group. Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open-label pilot study. Aliment Pharmacol. Ther., 2002, 16, 407-413.
154. Rai, R.; Sprengeler, P. A.; Elrod, K. C.; Young, W. B. Perspectives on factor Xa inhibition. Curr. Med. Chem., 2001, 8, 101-119.
155. Schaschke, N.; Dominik, A.; Matschiner, G.; Sommerhoff, C.P. Bivalent inhibition of beta-tryptase: distance scan of neighboring subunits by dibasic inhibitors. Bioorg. Med. Chem. Lett., 2002, 12, 985-988.
156. Slusarchyk, W.A.; Bolton, S.A.; Hartl, K. S.; Huang, M.-H.; Jacobs, G.; Meng, W.; Ogletree, M. L.; Pi, Z.; Schumacher, W.A.; Seiler, S.M.; Sutton, J.C.; Treuner, U.; Zahler, R.; Zhao, G.; Bisacchi, G.S.: Synthesis of potent and highly selective inhibitors of human tryptase. Bioorg. Med. Chem. Lett., 2002, 12, 3235-3238.
157. Sutton, J.C.; Bolton, S.A.; Hartl, K.S.; Huang, M.-H.; Jacobs, G.; Meng, W.; Ogletree, M.L.; Pi, Z.; Schumacher, W.A.; Seiler, S.M.; Slusarchyk, W.A.; Treuner, U.; Zahler, R.; Zhao, G.; Bisacchi, G.S.: Synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors. Bioorg. Med. Chem. Lett., 2002, 12, 3229-3233.
158. Sutton, J.C.; Bolton, S.A.; Davis, M.E.; Hartl, K.S.; Jacobson, B.; Mathur, A.; Ogletree, M.L.; Slusarchyk, W.A.; Zahler, R.; Seiler, S.M.; Bisacchi, G.S.: Solid-phase synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors. Bioorg. Med. Chem. Lett., 2004, 14, 2233-2239.
159. Bisacchi, G.S.; Sutton, J.C.; Slusarchyk, W.A.; Treuner, U.; Zhao, G. Beta lactam compounds and their use as inhibitors of tryptase. US Patent 20040147502; July 29, 2004.
160. Zhao, G.; Bolton, S.A.; Kwon, C.; Hartl, K.S.; Seiler, S.M.; Slusarchyk, W.A.; Sutton, J.C.; Bisacchi, G.S.: Synthesis of potent and se lective 2-azepanone inhibitors of human tryptase. Bioorg. Med. Chem. Lett., 2004, 14, 309-312.
161. Vaz, R.J.; Gao, Z.; Pribish, J.; Chen, X.; Levell, J.; Davis, L.; Albert, E.; Brollo, M.; Ugolini, A.; Cramer, D.M.; Cairns, J.; Sides, K.; Liu, F.; Kwong, J.; Kang, J.; Rebello, S.; Elliot, M.; Lim, H.; Chellaraj, V.; Singleton, R.W.; Li, Y. Design of bivalent ligands using hydrogen bond linkers: synthesis and evaluation of inhibitors for human beta-tryptase. Bioorg. Med. Chem. Lett., 2004, 14, 6053-6056.
162. Hopkins, C.; Neuenschwander, K.; Scotese, A.; Jackson, S.; Nieduzak, T.; Pauls, H.; Liang, G.; Sides, K.; Cramer, D.; Cairns, J.; Maignan, S.; Mathieu, M. Novel pyrazinone inhibitors of mast cell tryptase: synthesis and SAR evaluation. Bioorg. Med. Chem. Lett., 2004, 14, 4819-4823.
163. Levell, J.; Astles, P.; Eastwood, P.; Cairns, J.; Houille, O.; Aldous, S.; Merriman, G.; Whiteley, B.; Pribish, J.; Czekaj, M.; Liang, G.; Maignan, S.; Guilloteau, J.-P.; Dupuy, A.; Davidson, J.; Harrison, T.; Morley, A.; Watson, S.; Fenton, G.; McCarthy, C.; Romano, J.; Mathew, R.; Engers, D.; Gardyan, M.; Sides, K.; Kwong, J.; Tsay, J.; Rebello, S.; Shen, L.; Wang, J.; Luo, Y.; Giardino, O.; Lim, H.-K.; Smith, K.; Pauls, H. Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of betaII tryptase. Bioorg. Med. Chem., 2005, 13, 2859-2872.
164. Hopkins, C.R.; Czekaj, M.; Kaye, S.S.; Gao, Z.; Pribish, J.; Pauls, H.; Liang, G.; Sides, K.; Cramer, D.; Cairns, J.; Luo, Y.; Lim, H.-K.; Vaz, R.; Rebello, S.; Maignan, S.; Dupuy, A.; Mathieu, M.; Levell, J. Design, synthesis, and biological activity of potent and selective inhibitors of mast cell tryptase. Bioorg. Med. Chem. Lett., 2005, 15, 2734-2737.
165. Liang, G.; Choi-Sledeski, Y.M.; Poli, G.; Chen, X.; Shum, P.; Minnich, A.; Wang, Q.; Tsay, J.; Sides, K.; Cairns, J.; Stoklosa, G.; Nieduzak, T.; Zhao, Z.; Wang, J.; Vaz, R.J.: A conformationally constrained inhibitor with an enhanced potency for β-tryptase and stability against semicarbazide-sensitive amine oxidase (SSAO). Bioorg. Med. Chem. Lett., 2010, 20, 6721-6724.
166. Astles, P.C.; Eastwood, P.R.; Houille, O.; Levell, J.; Pauls, H.; Czekaj, M.; Liang, G.; Gong, Y.; Pribish, J.; Neuenschwander, K. Chemical Compounds. US Patent 6977263B2; December 20, 2005.
167. Sperandio, D.; Tai, V.W.F.; Lohman, J.; Hirschbein, B.; Mendonca, R.; Lee, C.-S.; Spencer, J.R.; Janc, J.; Nguyen, M.; Beltman, J.; Sprengeler, P.; Scheerens, H.; Lin, T.; Liu, L.; Gadre, A.; Kellogg, A.; Green, M.J.; McGrath, M. E.: Novel, potent, selective, and orally bioavailable human betaII-tryptase inhibitors. Bioorg. Med. Chem. Lett., 2006, 16, 4085-4089.
168. Katz, B.A.; Clark, J.M.; Finer-Moore, J.S.; Jenkins, T.E.; Johnson, C.R.; Ross, M.J.; Luong, C.; Moore, W. R.; Stroud, R.M. Design of potent selective zinc-mediated serine protease inhibitors. Nature, 1998, 391, 608-612.
169. Katz, B.A.; Spencer, J.R.; Elrod, K.; Luong, C.; Mackman, R.L.; Rice, M.; Sprengeler, P.A.; Allen, D.; Janc, J. Contribution of multicentered short hydrogen bond arrays to potency of active sitedirected serine protease inhibitors. J. Am. Chem. Soc., 2002, 124, 11657-11668.
170. Katz, B.A.; Elrod, K.; Verner, E.; Mackman, R.L.; Luong, C.; Shrader, W.D.; Sendzik, M.; Spencer, J.R.; Sprengeler, P.A.; Kolesnikov, A.; Tai, V.W.F.; Hui, H.C.; Guy Breitenbucher, J.; Allen, D.; Janc, J.W. Elaborate manifold of short hydrogen bond arrays mediating binding of active site-directed serine protease inhibitors. J. Mol. Biol., 2003, 329, 93-120.
171. Katz, B.A.; Luong, C.; Ho, J.D.; Somoza, J. R.; Gjerstad, E.; Tang, J.; Williams, S.R.; Verner, E.; Mackman, R.L.; Young, W.B.; Sprengeler, P.A.; Chan, H.; Mortara, K.; Janc, J.W.; McGrath, M.E.: Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA). J. Mol. Biol., 2004, 344, 527-547.
172. Yu, W.; Dener, J.M.; Dickman, D.A.; Grothaus, P.; Ling, Y.; Liu, L.; Havel, C.; Malesky, K.; Mahajan, T.; O'Brian, C.; Shelton, E.J.; Sperandio, D.; Tong, Z.; Yee, R.; Mordenti, J.J. Identification of metabolites of the tryptase inhibitor CRA-9249: observation of a metabolite derived from an unexpected hydroxylation pathway. Bioorg. Med. Chem. Lett., 2006, 16, 4053-4058.
173. Miyazaki, Y.; Kato, Y.; Manabe, T.; Shimada, H.; Mizuno, M.; Egusa, T.; Ohkouchi, M.; Shiromizu, I, Matsusue, T.; Yamamoto, I.: Synthesis and evaluation of 4-substituted benzylamine derivatives as beta-tryptase inhibitors. Bioorg. Med. Chem. Lett., 2006, 16, 2986-2990.
174. Matter, H.; Nazaré, M.; Guessregen, S.; Will, D.W.; Schreuder, H.; Bauer, A.; Urmann, M.; Ritter, K.; Wagner, M.; Wehner, V. Evidence for C-Cl/C-Br…pi interactions as an important contribution to protein-ligand binding affinity. Angewandte Chemie, Int. Edition, 2009, 48, 2911-2916.