Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 15, 2009, Pages 4034-4041

  Shi, Yan ^a   Zhang, Jing ^a   Shi, Mengxiao ^a   O'Connor, Stephen P ^a   Bisaha, Sharon N ^a   Li, Chi ^a   Sitkoff, Doree ^a   Pudzianowski, Andrew T ^a   Chong, Saeho ^a   Klei, Herbert E ^a   Kish, Kevin ^a   Yanchunas Jr , Joseph ^a   Liu, Eddie C K ^a   Hartl, Karen S ^a   Seiler, Steve M ^a   Steinbacher, Thomas E ^a   Schumacher, William A ^a   Atwal, Karnail S ^a   Stein, Philip D ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

Bioavailable; Bioisostere; Cyanoguanidine; Factor Xa inhibitor; Ketene aminal; Thiourea

Indexed keywords

1 METHYL 3 PHEPHENYL 2 CYANOGUANIDINE; ANTITHROMBOCYTIC AGENT; BLOOD CLOTTING FACTOR 10A INHIBITOR; BMS 269223; DICYANODIAMIDE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTERY THROMBOSIS; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG STRUCTURE; DRUG SUBSTITUTION; HYDROGEN BOND; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; VEIN THROMBOSIS; X RAY ANALYSIS;

ADMINISTRATION, ORAL; ANIMALS; ANTITHROMBIN III; BENZOFURANS; CHEMISTRY, PHARMACEUTICAL; CRYSTALLOGRAPHY, X-RAY; DOGS; GUANIDINES; HAPLORHINI; HUMANS; INHIBITORY CONCENTRATION 50; KINETICS; LACTAMS; LIGANDS; MODELS, CHEMICAL; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; THIOUREA;

ANIMALIA;

EID: 67649946941     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.06.014     Document Type: Article

References (39)

1. For reviews, see:. Kunitada S., Nagahara T., and Hara T. Handbook Exp. Pharmacol. (1998) 397
2. Vacca J.P. Ann. Rep. Med. Chem. 33 (1998) 81
3. Zhu B.-Y., and Scarborough R.M. Curr. Opin. Cardiovacs., Pulmon., Ren. Investig. Drugs 1 (1999) 63
4. Ewing W.R., Pauls H.W., and Spada A.P. Drugs Future 24 (1999) 771
5. Fevig J.M., and Wexler R.R. Ann. Rep. Med. Chem. 34 (1999) 81
6. Betz A. Exp. Opin. Ther. Patent 11 (2001) 1007
7. Davie E.W., Fujikawa K., and Kisiel W. Biochemistry 30 (1991) 10363
8. Butenas S., Van 't Veer C., Cawthern K., Brummel K.E., and Mann K.G. Blood Coagul. Fibrin. 11 (2000) S9
9. Wong P.C., Watson C.A., Crain E.J., Ogletree M.L., Wexler R.R., Lam P.Y.S., Pinto D.J., and Knabb R.M. J. Thromb. Haemost. 5 (2007) Abstr. 1315
10. For Apixaban, see:. Lassen M.R., Davidson B.L., Gallus A., Pineo G., Ansell J., and Deitchman D. J. Thromb. Haemost. 5 (2007) 2368
11. 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., and Lam P.Y.S. J. Med. Chem. 50 (2007) 5339
12. Wong P.C., Crain E.J., Xin B., Wexler R.R., Lam P.Y., Pinto D.J., Luettgen J.M., and Knabb R.M. J. Thromb. Haemost. 6 (2008) 820
13. For Rivaroxaban, see:. Roehrig S., Straub A., Pohlmann J., Lampe T., Pernerstorfer J., Schlemmer K.-H., Reinemer P., and Perzborn E. J. Med. Chem. 48 (2005) 5900
14. Eriksson B.I., Borris L., Dahl O.E., Haas S., Huisman M.V., Kakkar A.K., Misselwitz F., and Kaelebo P. J. Thromb. Haemost. 4 (2006) 121
15. Kubitza D., Becka M., Wensing G., Voith B., and Zuehlsdorf M. Eur. J. Clin. Pharmacol. 61 (2005) 873
16. Turpie A.G.G., Fisher W.D., Bauer K.A., Kwong L.M., Irwin M.W., Kalebo P., Misselwitz F., and Gent M. J. Thromb. Haemost. 3 (2005) 2479
17. For LY517717, see:. Agnelli G., Haas S.K., Krueger K.A., Bedding A.W., and Brandt J.T. ASH Ann. Meet. Abstr. 106 (2005) 278
18. Hampton T. JAMA J. Am. Med. Assoc. 295 (2006) 743
19. Liebeschuetz J.W., Jones S.D., Wiley M.E., and Young S.C. Struct.-Based Drug Discovery (2006) 173
20. Bisacchi G.S., Stein P.D., Gougoutas J.Z., Hartl K.S., Lawrence R.M., Liu E.C., Pudzianowski A.T., Schumacher W.A., Sitkoff D., Steinbacher T.E., Sutton J., Zhang Z., and Seiler S.M. Lett. Drug Des. Discovery 2 (2005) 625
21. 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., and Zahler R. Bioorg. Med. Chem. Lett. 15 (2005) 5453
22. Silverman R.B. The Organic Chemistry of Drug Design and Drug Action (1992), Academic, New York 159-165
23. Durant G.J., Emmett J.C., Ganellin C.R., Miles P.D., Parsons M.E., Prain H.D., and White G.R. J. Med. Chem. 20 (1977) 901
24. Black J.W., Durant G.J., and Ganellin C.R. Nature 248 (1974) 65
25. Bradshaw J.C., Ganellin C.R., and Parsons M.E. J. Int. Med. Res. 3 (1975) 86
26. Domschke W., Lux G., and Domschke D. Lancet 8111 (1979) 320
27. All calculations were done at the RI-MP2/6-31+G(d,p) level of theory with the q-chem 3.0 program system:. Feyereisen M., Fitzgerald G., and Komornicki A. Chem. Phys. Lett. 208 (1993) 359
28. Shao, Y.; Fusti-Molnar, L.; Jung, Y.; Kussmann, J.; Ochsenfeld, C.; Brown, S. T.; Gilbert, A. T. B.; Slipchenko, L. V.; Levchenko, S. V.; O'Neill, D. P.; Distasio, R. A. Jr.; Lochan, R. C.; Wang, T.; Beran, G. J. O.; Besley, N. A.; Herbert, J. M.; Lin, C. Y.; Van Voorhis, T.; Chien, S. H.; Sodt, A; Steele, R. P.; Rassolov, V. A.; Maslen, P. E.; Korambath, P. P.; Adamson, R. D.; Austin, B.; Baker, J.; Byrd, E. F. C.; Dachsel, H.; Doerksen, R. J.; Dreuw, A.; Dunietz, B. D.; Dutoi, A. D.; Furlani, T. R.; Gwaltney, S. R.; Heyden, A.; Hirata, S.; Hsu, C.-P.; Kedziora, G.; Khalliulin, R. Z.; Klunzinger, P.; Lee, A. M.; Lee, M. S.; Liang, W.; Lotan, I.; Nair, N.; Peters, B.; Proynov, E. I.; Pieniazek, P. A.; Rhee, Y. M.; Ritchie, J.; Rosta, E.; Sherrill, C. D.; Simmonett, A. C.; Subotnik, J. E.; Woodcock, H. L. III; Zhang, W.; Bell, A. T.; Chakraborty, A. K.; Chipman, D. M.; Keil, F. J.; Warshel, A.; Hehre, W. J.; Schaefer III, H. F.; Kong, J.; Krylov, A. I.; Gill, P. M. W.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2006, 8, 3172.
29. For detailed assay methods, see:. Shi Y., Sitkoff D., Zhang J., Klei H.E., Kish K., Liu E.C.-K., Hartl K.S., Seiler S.M., Chang M., Huang C., Youssef S., Steinbacher T.E., Schumacher W.A., Grazier N., Pudzianowski A., Apedo A., Discenza L., Yanchunas Jr. J., Stein P.D., and Atwal K.S. J. Med. Chem. 51 (2008) 7541
30. 50's probably due to plasma protein bounding. For example, compound 4 is 98.7% plasma protein bound in human plasma. See Ref. 8.
31. Compound 39 was synthesized much later after the discovery of compound 4, and it was not fully characterized in vivo.
32. The X-ray crystal structure coordinates of 4 in human factor Xa have been deposited in the Protein Data Bank (PDB code 3HPT).
33. Contours calculated using GRID (version 22a, Molecular Discovery) with methyl probe C3, contoured at interaction energy level of -2.5 kcal/mol:. Goodford P.J. J. Med. Chem. 28 (1985) 849
34. Some examples are ascension codes 1lpk, 1nfu, 1nfy, 1xka, 1xkb, 1wu1, 2h9e.
35. Atwal K.S., Ahmed S.Z., and O'Reilly B.C. Tetrahedron Lett. 30 (1989) 7313
36. 4; gradient-linear, 50% A to 0% A over 8 min then hold.
37. Maron D.M., and Ames B.N. Mutat. Res. 113 (1983) 173
38. + channel (site 2) (r), Cl-channel (r), NE transporter (h), DA transporter (r), GABA transporter (r), Choline transporter (r). For details regarding the specific receptors and experimental conditions see: http://www.cerep.fr/Cerep/Users/pages/catalog/binding/catalog.asp.
39. Arterial and venous thrombosis were performed in pentobarbital-anesthetized male Sprague Dawley rats as described in: Schumacher, W. A.; .Heran, C. L.: Steinbacher, T. E. J. Cardiovas. Pharmacol. 1996, 28, 19. To measure ex vivo clotting time, rats were fasted overnight and anesthetized with sodium pentobarbital (50 mg/kg, ip). Catheters were placed in a jugular vein for iv dosing, and into the duodenum at the level of the bile duct for intraduodenal dosing. Arterial blood samples were withdrawn from a carotid artery catheter into 3.8% Na-citrate (1/10; v/v) to measure prothrombin time by the standard procedure described for Dade Thromboplastin-C reagent (Baxter Healthcare Corp., Miami, FL) (Baxter Healthcare Corp., Miami,FL), which had an international sensitivity index of 2.0 for the mechanical clot detection method employed. The dosing solution for these studies was 10% ethanol/90% PEG300 in a volume of 1 mL/kg for bolus iv or intraduodenal dosing, and at 1 mL/kg/h for sustaining iv infusion.