Structure and property based design of factor Xa inhibitors: Pyrrolidin-2-ones with biaryl P4 motifs

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 1, 2008, Pages 23-27

  Young, Robert J ^a   Borthwick, Alan D ^a   Brown, David ^a   Burns Kurtis, Cynthia L ^b   Campbell, Matthew ^a   Chan, Chuen ^a   Charbaut, Marie ^a   Chung, Chun wa ^a   Convery, Máire A ^a   Kelly, Henry A ^a   Paul King, N ^a   Kleanthous, Savvas ^a   Mason, Andrew M ^a   Pateman, Anthony J ^a   Patikis, Angela N ^a   Pinto, Ivan L ^a   Pollard, Derek R ^a   Senger, Stefan ^a   Shah, Gita P ^a   Toomey, John R ^b   Watson, Nigel S ^a   Weston, Helen E ^a   more..

^a GLAXOSMITHKLINE   (United Kingdom)

^b GLAXOSMITHKLINE   (United States)

Author keywords

Factor Xa; Oral inhibitors; QSAR analysis

Indexed keywords

2 PYRROLIDONE DERIVATIVE; ANTICOAGULANT AGENT; BLOOD CLOTTING FACTOR 10A INHIBITOR; SULFONAMIDE;

ANTICOAGULATION; ARTICLE; DRUG ACTIVITY; DRUG DESIGN; DRUG STRUCTURE; DRUG SYNTHESIS; NONHUMAN;

ANIMALS; ANTICOAGULANTS; DRUG DESIGN; FACTOR XA; MALE; MODELS, MOLECULAR; PYRROLIDINONES; RATS; RATS, SPRAGUE-DAWLEY; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 37549065150     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.11.023     Document Type: Article

References (30)

1. Quan M.L., and Smallheer J.M. Curr. Opin. Drug Discovery Devel. 7 (2004) 460
2. Gould W.R., and Leadley R. J. Curr. Pharm. Des. 9 (2003) 2337
3. Hirsh J., O'Donell M., and Weitz J.I. Blood 105 (2005) 453
4. Golino P., Loffredo F., Riegler L., Renzullo E., and Cocchia R. Curr. Opin. Invest. Drugs 6 (2005) 298
5. Alexander J.H., and Singh K.P. Am. J. Cardiovasc. Drugs 5 (2005) 279
6. Saiah E., and Soares C. Curr. Top. Med. Chem. 5 (2005) 1677
7. Weitz J.I., and Linkins L.-A. Exp. Opin. Invest. Drugs 16 (2007) 271
8. Spyropoulos A.C. Exp. Opin. Invest. Drugs 16 (2007) 431
9. Watson N.S., Brown D., Campbell M., Chan C., Chaudry L., Convery M.A., Fenwick R., Hamblin J.N., Haslam C., Kelly H.A., King N.P., Kurtis C.L., Leach A.R., Manchee G.R., Mason A.M., Mitchell C., Patel C., Patel V.K., Senger S., Shah G.P., Weston H.E., Whitworth C., and Young R.J. Bioorg. Med. Chem. Lett. 16 (2006) 3784
10. Chan C., Borthwick A.D., Brown D., Campbell M., Chaudry L., Chung C.-W., Convery M.A., Hamblin J.N., Johnstone L., Kelly H.A., Kleanthous S., Kurtis C.L., Patikis A., Patel C., Pateman A.J., Senger S., Shah G.P., Toomey J.R., Watson N.S., Weston H.E., Whitworth C., Young R.J., and Zhou P. J. Med. Chem. 50 (2007) 1546
11. Young R.J., Campbell M., Borthwick A.D., Brown D., Burns-Kurtis C.L., Chan C., Convery M.A., Crowe M.C., Dayal S., Diallo H., Kelly H.A., King N.P., Kleanthous S., Mason A.M., Mordaunt J.E., Patel C., Pateman A.J., Senger S., Shah G.P., Smith P.W., Watson N.S., Weston H.E., and Zhou P. Bioorg. Med. Chem. Lett. 16 (2006) 5953
12. McMartin, C. FLO/QXP Molecular Modeling software. Thistlesoft, Colebrook, CT, USA.
13. Other groups have reported independently on series of fXa inhibitors incorporating biaryl P4 ligands, for example. Kohrt J.T., Filipski K.J., Cody W.L., Bigge C.F., La F., Welch K., Dahring T., Bryant J.W., Leonard D., Bolton G., Narasimhan L., Zhang E., Peterson J.T., Haarer S., Sahasrabudhe V., Janiczek N., Desiraju S., Hena M., Fiakpui C., Saraswat N., Sharma R., Sun S., Maiti S.N., Leadley R., and Edmunds J.J. Bioorg. Med. Chem. 14 (2006) 4379
14. Pinto D.J.P., Galemmo R.A., Quan M.L., Orwat M.J., Clark C., Li R., Wells B., Woerner F., Alexander R.S., Rossi K.A., Smallwood A., Wong P.C., Luettgen J.M., Rendina A.R., Knabb R.M., He K., Wexler R.R., and Lam P.Y.S. Bioorg. Med. Chem. Lett. 16 (2006) 5584
15. 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., Aunggst B.J., Wright M.R., Knabb R.M., Wong P.C., Wexler R.R., and Lam P.Y.S. J. Med. Chem. 44 (2001) 566
16. for further examples see Ref. 1 and cited references.
17. Bell I.M., Beshore D.C., Gallicchio S.N., and Williams T.M. Tetrahedron Lett. 41 (2000) 1141
18. 19F NMR of Mosher amide derivatives of particular deblocked amines analogous to 7 or chiral hplc analysis of specific final compounds.
19. The majority of aryl bromides and boronic acids combinations employed were available from the GSK monomer collection; or prepared as described in Borthwick, A. D.; Chan, C.; Kelly, H. A.; King, N. P.; Kleanthous, S.; Mason, A. M.; Pinto, I. L.; Pollard, D. R.; Senger, S.; Shah, G. P.; Watson, N. S.; Young, R. J. WO 03053925 A1, 2003.
20. The stereochemistry of the 3-amino linkage we believe was most probably racemised under the strongly basic cross-coupling conditions. However, the preferred (3S)-enantiomer, anticipated from docking studies, was clearly evident in the structures bound within fXa when co-crystallised from the racemates. A fuller exploration of the preferred stereochemistry of similar biaryl molecules is discussed in more detail in the accompanying paper.
21. 16.
22. Factor Xa inhibitory activities were largely determined using Rhodamine 110, bis-(CBZ-glycylglycyl)-l-arginine amide as fluorogenic substrate, with the others using N-α-Z-d-Arg-Gly-Arg-p-nitroanilide as chromogenic substrate; details are described in Ref. 3b. For compounds tested in both assays, comparable levels of activity were observed.
23. Anticoagulant activities were determined in the prothrombin time (PT) assay; see Ref. 3b.
24. 7.4, were calculated using Advanced Chemistry Development software v8.0.
25. 7.4 values, for details see. Valkó K., Du C.M., Bevan C., Reynolds D.P., and Abraham M.H. Curr. Med. Chem. 8 (2001) 1137
26. high throughput human serum albumin binding was measured as described in. Valkó K., Numhuck S., Bevan C., Abraham M.H., and Reynolds D.P. J. Pharm. Sci. 92 (2003) 2236
27. 3,4 were generally more tightly bound to specific human serum albumin sites and had reduced fXa on-rates, consistent with their relatively poorer translation of intrinsic potency into plasma-based activity. Chung, C.-W. et al. manuscript in preparation.
28. free of 0.241, using procedures described in Ref. 3b. Co-ordinates are deposited in the protein data bank with code 2vh6.
29. m were used from. Hansch C., Leo A., and Taft W. Chem. Rev. 91 (1991) 165
30. The formulation used for both iv and po dosing was a 5:95% (v/v) mixture of DMSO and 50:50 PEG-200:sterile water. Serial blood samples were collected into heparinised containers at various time-points and blood centrifuged to yield plasma. These studies used two animals for each (iv/po) leg.