d-Phenylglycinol-derived non-covalent factor Xa inhibitors: Effect of non-peptidic S4 linkage elements on affinity and anticoagulant activity

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 21, 2007, Pages 5801-5805

  Klimkowski, Valentine J ^a   Watson, Brian M ^a   Wiley, Michael R ^a   Liebeschuetz, John ^b   Franciskovich, Jeffry B ^a   Marimuthu, Jothirajah ^a   Bastian, Jolie A ^a   Sall, Daniel J ^a   Smallwood, Jeffrey K ^a   Chirgadze, Nikolay Y ^a   Smith, Gerald F ^a   Foster, Ronald S ^a   Craft, Trelia ^a   Sipes, Philip ^a   Chastain, Marcia ^a   Sheehan, Scott M ^a  

^a ELI LILLY AND COMPANY   (United States)

^b Tularik Ltd   (United Kingdom)

Author keywords

Coagulation cascade; Factor Xa; Non covalent inhibitors; Serine protease inhibitors

Indexed keywords

AMIDE; ANTICOAGULANT AGENT; BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING FACTOR 10A INHIBITOR; DEXTRO PHENYLGLYCINAMIDE; SERINE PROTEINASE INHIBITOR; UNCLASSIFIED DRUG;

ANTICOAGULATION; ARTICLE; BINDING AFFINITY; BLOOD CLOTTING; COMPUTER MODEL; CRYSTAL STRUCTURE; DOG; DRUG TARGETING; HUMAN; HYDROGEN BOND; IN VITRO STUDY; MOLECULAR INTERACTION; MONKEY; NONHUMAN; PLASMA; RAT; SPECIES DIFFERENCE; STRUCTURE ACTIVITY RELATION; THROMBOSIS; THROMBOSIS PREVENTION; X RAY CRYSTALLOGRAPHY;

ANTICOAGULANTS; CRYSTALLOGRAPHY, X-RAY; FACTOR XA; GLYCINE; MODELS, MOLECULAR; PEPTIDES; SERINE PROTEINASE INHIBITORS;

EID: 34648817589     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.08.051     Document Type: Article

References (23)

1. Agnelli G., and Sonaglia F. Haematologica 87 (2002) 757-770
2. Zhu B.-Y., and Scarborough R.M. Ann. Rep. Med. Chem. 38 (2000) 83-102
3. Turpie A.G. Am. J. Cardiol. 82 (1998) 11L-14L
4. Wiley M.R., and Fisher M.J. Expert Opin. Ther. Pat. 7 (1997) 1265-1282
5. Schulman S., Wahlander K., Lundstrom T., Clason S.B., and Eriksson M.D. N. Eng. J. Med. 18 (2003) 349 1713
6. Zhu B.-Y., and Scarborough R.M. Curr. Opin. Cardiovasc. Pulm., & Ren. Inv. Drugs 1 (1999) 63
7. Kubitza D., and Haas S. Expert Opin. Inv. Drugs 15 (2006) 843
8. Casimiro-Garcia A., Dudley D.A., Heemstra R.J., Filipski K.J., Bigge C.F., and Edmunds J.J. Expert Opin. Ther. Pat. 16 (2006) 119
9. Gould W.R., and Leadley R.J. Curr. Pharm. Des. 9 (2003) 2337
10. Sheehan S.M., Masters J.J., Wiley M.R., Young S.C., Liebeschuetz J.W., Jones S.D., Murray C.W., Franciskovich J.B., Engel D.B., Weber W.W., Marimuthu J., Kyle J.A., Smallwood J.K., Farmen M.W., and Smith G.F. Bioorg. Med. Chem. Lett. 13 (2003) 2255
11. Jones, S. D.; Wiley, M. R.; Masters, J. J.; Young, S. C.; Liebeschuetz, J. W.; Murray, C. W.; Richards, S. J.; Webber, W. W. III; Marimuthu, J.; Kyle, J.; Sheehan, S.; Watson, B.; Smallwood, J. K.; Foster, R.; Craft, T. J.; Gifford-Moore, D.; Towner, R. D.; Smith, G. F. Abstracts of Papers, Part MEDI-231 225th National Meeting of the American Chemical Society, New Orleans, LA, March 23-27, 2003; American Chemical Society Washington, DC, 2003.
12. 15 Using residue identity, the trypsin structure complex was superimposed onto the factor Xa protein structure, and then the ligand coordinates of the former were extracted and modified. The initial structure of 1 was then inserted into the factor Xa structure. Molecular modeling then proceeded in a similar fashion as detailed previously in Ref. 9a. All molecular modeling was performed with QUANTA and CHARMm, version 98 (Accelrys Inc., San Diego, CA 92121).
13. For detailed experimental procedures: Liebeschuetz, J. W.; Sheehan, S. M.; Watson, B. M. PCT Int. Appl. WO2004060872.
14. Compound 2 has >1000× selectivity with respect to the following enzymes: Thrombin, Plasmin, Bovine Trypsin, Urokinase, aPC, Kallikrein, and tPA.
15. Herron D.K., Goodson Jr. T., Wiley M.R., Weir L.C., Kyle J.A., Yee Y.K., Tebbe A.L., Tinsley J.M., Mendel D., Masters J.J., Franciskovich J.B., Sawyer J.S., Beight D.W., Ratz A.M., Milot G., Hall S.E., Klimkowski V.J., Wikel J.H., Eastwood B.J., Towner R.D., Gifford-Moore D.S., Craft T.J., and Smith G.F. J. Med. Chem. 43 (2000) 859
16. Smith G.F., Gifford-Moore D.S., Craft T.J., Chirgadze N.K., Ruterbories K.J., Lindstrom T.D., and Satterwhite J.H. In: Piffare R. (Ed). New Anticoagulants for the Cardiovascular Patient (1997), Hanley & Belfus Publishers, Philadelphia 265-300
17. ass data generated in this fashion from a single experiment have been determined to have a minimum significant ratio of 2.13.
18. Bland J.M., and Altman D.G. Lancet 1 (1986) 307
19. We have found that the majority of Xa binding affinity results from one enantiomer (unpublished results), and test inhibitors as racemates when it is synthetically expedient to do so.
20. Rai R., Sprengeler P.A., Elrod K.C., and Young W.B. Curr. Med. Chem. 8 (2001) 101
21. The minimum significant ratio for this assay has been determined to be 2.26.
22. Brandstetter H., Kuhne A., Bode W., Huber R., von der Saal W., Wirthersohn K., and Engh R.A. J. Biol. Chem. 271 (1996) 29988
23. Liebeschuetz J.W., Jones S.D., Morgan P.J., Murray C.W., Rimmer A.D., Roscoe J.M.E., Waszkowycs B., Welsh P.M., Wylie W.A., Young S.C., Martin H., Mahler J., Brady L., and Wilkinson K. J. Med. Chem. 45 (2002) 1221