5,5-trans lactone-containing inhibitors of serine proteases: Identification of a novel, acylating thrombin inhibitor

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 21, 1998, Pages 2955-2960

  Finch, Harry ^a   Pegg, Neil A ^a   McLaren, Jessica ^a   Lowdon, Andrew ^a   Bolton, Richard ^a   Coote, Steve J ^a   Dyer, Ulrich ^a   Montana, John G ^a   Owen, Martin R ^a   Dowle, Mike ^a   Buckley, Doreen ^a   Ross, Barry C ^a   Campbell, Callum ^a   Dix, Clive ^a   Mooney, Christopher ^a   Man Tang, Chi ^a   Patel, Champa ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CHYMOTRYPSIN INHIBITOR; ELASTASE INHIBITOR; LACTONE DERIVATIVE; LEUKOCYTE ELASTASE; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR; THROMBIN INHIBITOR; TRITERPENE DERIVATIVE; TRYPSIN INHIBITOR;

ACYLATION; ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN;

BINDING SITES; HUMANS; KINETICS; LACTONES; SERINE PROTEINASE INHIBITORS; THROMBIN;

LANTANA CAMARA;

EID: 17144468683     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00531-9     Document Type: Article

References (33)

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5. 4. For some recent references see; Oh, Y.S., Yun, M ; Hwang, S Y.; Hong, S.; Shin, Y.; Lee, K.; Yoon, K.H.; Yoo, Y J.; Kim, D.S.; Lee, S.H.; Lee, Y.H.; Park, H.D.; Lee, C H.; Lee, S K ; Kim, S. Bioorg Med Chem Lett , 1998, 8, 631, Fevig, J.M ; Bunak, J ,Jr , Cacciola, J ; Alexander, R S ; Kettner, C A., Knabb, R.M.; Pruitt, J R ; Weber, P C., Wexler, R.R. Bioorg Med Chem Lett , 1998, 8, 301; Brady, S.F.; Stauffer, K.J.; Lumma, W.C ; Smith, G M.; Ramjit, H.G ; Lewis, S.D.; Lucas, B.J ; Gardell, S J.; Lyle, E A.; Appleby, S.D , Cook, J.J , Holahan, M A ; Strameri, M T., Lynch, J J , Jr ; Lin, J H ; Chen, I.W., Vastag, K., Naylor-Olsen, A M.; Vacca, J.P. J Med Chem., 1998, 41, 401 ; Feng, D-M., Gardell, S J., Lewis, S D , Bock, M.G.; Chen, Z., Freidinger, R.M., Naylor-Olsen, A.M.; 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, JP. J Med Chem., 1997, 40, 3726, Sall, D J , Bastian, J A., Briggs, S.L ; Buben, J.A.; Chirgadze, N Y., Clawson, D.K.; Denney, M.L ; Giera, D D., Gifford-Moore, D.S.; Harper, R.W , Hauser, K L ; Khlimkowski, V.J.; Kohn, T.J.; Lin, H-S.; McCowan, J.R., Palkowitz, A.D.; Smith, G.F., Takeuchi, K.; Thrasher, K J , Tinsley, J M ; Utterback, B G., Yan, S-C.B.; Zhang, M J Med Chem., 1997, 40, 3489, Tucker, T J , Lumma, W C.; Lewis, S D.; Gardell, S.J ; Lucas, B.J.; Sisko, J.T.; Lynch, J.J.; Lyle, E.A ; Baskin, E.P , Woltmann, R.F.; Appleby, S.D., Chen, I-W ; Dancheck, K B ; Naylor-Olsen, A M ; Krueger, J.A ; Cooper, C.M.; Vacca, J.P. J Med Chem , 1997, 40, 3687.
6. 4. For some recent references see; Oh, Y.S., Yun, M ; Hwang, S Y.; Hong, S.; Shin, Y.; Lee, K.; Yoon, K.H.; Yoo, Y J.; Kim, D.S.; Lee, S.H.; Lee, Y.H.; Park, H.D.; Lee, C H.; Lee, S K ; Kim, S. Bioorg Med Chem Lett , 1998, 8, 631, Fevig, J.M ; Bunak, J ,Jr , Cacciola, J ; Alexander, R S ; Kettner, C A., Knabb, R.M.; Pruitt, J R ; Weber, P C., Wexler, R.R. Bioorg Med Chem Lett , 1998, 8, 301; Brady, S.F.; Stauffer, K.J.; Lumma, W.C ; Smith, G M.; Ramjit, H.G ; Lewis, S.D.; Lucas, B.J ; Gardell, S J.; Lyle, E A.; Appleby, S.D , Cook, J.J , Holahan, M A ; Strameri, M T., Lynch, J J , Jr ; Lin, J H ; Chen, I.W., Vastag, K., Naylor-Olsen, A M.; Vacca, J.P. J Med Chem., 1998, 41, 401 ; Feng, D-M., Gardell, S J., Lewis, S D , Bock, M.G.; Chen, Z., Freidinger, R.M., Naylor-Olsen, A.M.; 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, JP. J Med Chem., 1997, 40, 3726, Sall, D J , Bastian, J A., Briggs, S.L ; Buben, J.A.; Chirgadze, N Y., Clawson, D.K.; Denney, M.L ; Giera, D D., Gifford-Moore, D.S.; Harper, R.W , Hauser, K L ; Khlimkowski, V.J.; Kohn, T.J.; Lin, H-S.; McCowan, J.R., Palkowitz, A.D.; Smith, G.F., Takeuchi, K.; Thrasher, K J , Tinsley, J M ; Utterback, B G., Yan, S-C.B.; Zhang, M J Med Chem., 1997, 40, 3489, Tucker, T J , Lumma, W C.; Lewis, S D.; Gardell, S.J ; Lucas, B.J.; Sisko, J.T.; Lynch, J.J.; Lyle, E.A ; Baskin, E.P , Woltmann, R.F.; Appleby, S.D., Chen, I-W ; Dancheck, K B ; Naylor-Olsen, A M ; Krueger, J.A ; Cooper, C.M.; Vacca, J.P. J Med Chem , 1997, 40, 3687.
7. 4. For some recent references see; Oh, Y.S., Yun, M ; Hwang, S Y.; Hong, S.; Shin, Y.; Lee, K.; Yoon, K.H.; Yoo, Y J.; Kim, D.S.; Lee, S.H.; Lee, Y.H.; Park, H.D.; Lee, C H.; Lee, S K ; Kim, S. Bioorg Med Chem Lett , 1998, 8, 631, Fevig, J.M ; Bunak, J ,Jr , Cacciola, J ; Alexander, R S ; Kettner, C A., Knabb, R.M.; Pruitt, J R ; Weber, P C., Wexler, R.R. Bioorg Med Chem Lett , 1998, 8, 301; Brady, S.F.; Stauffer, K.J.; Lumma, W.C ; Smith, G M.; Ramjit, H.G ; Lewis, S.D.; Lucas, B.J ; Gardell, S J.; Lyle, E A.; Appleby, S.D , Cook, J.J , Holahan, M A ; Strameri, M T., Lynch, J J , Jr ; Lin, J H ; Chen, I.W., Vastag, K., Naylor-Olsen, A M.; Vacca, J.P. J Med Chem., 1998, 41, 401 ; Feng, D-M., Gardell, S J., Lewis, S D , Bock, M.G.; Chen, Z., Freidinger, R.M., Naylor-Olsen, A.M.; 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, JP. J Med Chem., 1997, 40, 3726, Sall, D J , Bastian, J A., Briggs, S.L ; Buben, J.A.; Chirgadze, N Y., Clawson, D.K.; Denney, M.L ; Giera, D D., Gifford-Moore, D.S.; Harper, R.W , Hauser, K L ; Khlimkowski, V.J.; Kohn, T.J.; Lin, H-S.; McCowan, J.R., Palkowitz, A.D.; Smith, G.F., Takeuchi, K.; Thrasher, K J , Tinsley, J M ; Utterback, B G., Yan, S-C.B.; Zhang, M J Med Chem., 1997, 40, 3489, Tucker, T J , Lumma, W C.; Lewis, S D.; Gardell, S.J ; Lucas, B.J.; Sisko, J.T.; Lynch, J.J.; Lyle, E.A ; Baskin, E.P , Woltmann, R.F.; Appleby, S.D., Chen, I-W ; Dancheck, K B ; Naylor-Olsen, A M ; Krueger, J.A ; Cooper, C.M.; Vacca, J.P. J Med Chem , 1997, 40, 3687.
8. 4. For some recent references see; Oh, Y.S., Yun, M ; Hwang, S Y.; Hong, S.; Shin, Y.; Lee, K.; Yoon, K.H.; Yoo, Y J.; Kim, D.S.; Lee, S.H.; Lee, Y.H.; Park, H.D.; Lee, C H.; Lee, S K ; Kim, S. Bioorg Med Chem Lett , 1998, 8, 631, Fevig, J.M ; Bunak, J ,Jr , Cacciola, J ; Alexander, R S ; Kettner, C A., Knabb, R.M.; Pruitt, J R ; Weber, P C., Wexler, R.R. Bioorg Med Chem Lett , 1998, 8, 301; Brady, S.F.; Stauffer, K.J.; Lumma, W.C ; Smith, G M.; Ramjit, H.G ; Lewis, S.D.; Lucas, B.J ; Gardell, S J.; Lyle, E A.; Appleby, S.D , Cook, J.J , Holahan, M A ; Strameri, M T., Lynch, J J , Jr ; Lin, J H ; Chen, I.W., Vastag, K., Naylor-Olsen, A M.; Vacca, J.P. J Med Chem., 1998, 41, 401 ; Feng, D-M., Gardell, S J., Lewis, S D , Bock, M.G.; Chen, Z., Freidinger, R.M., Naylor-Olsen, A.M.; 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, JP. J Med Chem., 1997, 40, 3726, Sall, D J , Bastian, J A., Briggs, S.L ; Buben, J.A.; Chirgadze, N Y., Clawson, D.K.; Denney, M.L ; Giera, D D., Gifford-Moore, D.S.; Harper, R.W , Hauser, K L ; Khlimkowski, V.J.; Kohn, T.J.; Lin, H-S.; McCowan, J.R., Palkowitz, A.D.; Smith, G.F., Takeuchi, K.; Thrasher, K J , Tinsley, J M ; Utterback, B G., Yan, S-C.B.; Zhang, M J Med Chem., 1997, 40, 3489, Tucker, T J , Lumma, W C.; Lewis, S D.; Gardell, S.J ; Lucas, B.J.; Sisko, J.T.; Lynch, J.J.; Lyle, E.A ; Baskin, E.P , Woltmann, R.F.; Appleby, S.D., Chen, I-W ; Dancheck, K B ; Naylor-Olsen, A M ; Krueger, J.A ; Cooper, C.M.; Vacca, J.P. J Med Chem , 1997, 40, 3687.
9. 4. For some recent references see; Oh, Y.S., Yun, M ; Hwang, S Y.; Hong, S.; Shin, Y.; Lee, K.; Yoon, K.H.; Yoo, Y J.; Kim, D.S.; Lee, S.H.; Lee, Y.H.; Park, H.D.; Lee, C H.; Lee, S K ; Kim, S. Bioorg Med Chem Lett , 1998, 8, 631, Fevig, J.M ; Bunak, J ,Jr , Cacciola, J ; Alexander, R S ; Kettner, C A., Knabb, R.M.; Pruitt, J R ; Weber, P C., Wexler, R.R. Bioorg Med Chem Lett , 1998, 8, 301; Brady, S.F.; Stauffer, K.J.; Lumma, W.C ; Smith, G M.; Ramjit, H.G ; Lewis, S.D.; Lucas, B.J ; Gardell, S J.; Lyle, E A.; Appleby, S.D , Cook, J.J , Holahan, M A ; Strameri, M T., Lynch, J J , Jr ; Lin, J H ; Chen, I.W., Vastag, K., Naylor-Olsen, A M.; Vacca, J.P. J Med Chem., 1998, 41, 401 ; Feng, D-M., Gardell, S J., Lewis, S D , Bock, M.G.; Chen, Z., Freidinger, R.M., Naylor-Olsen, A.M.; 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, JP. J Med Chem., 1997, 40, 3726, Sall, D J , Bastian, J A., Briggs, S.L ; Buben, J.A.; Chirgadze, N Y., Clawson, D.K.; Denney, M.L ; Giera, D D., Gifford-Moore, D.S.; Harper, R.W , Hauser, K L ; Khlimkowski, V.J.; Kohn, T.J.; Lin, H-S.; McCowan, J.R., Palkowitz, A.D.; Smith, G.F., Takeuchi, K.; Thrasher, K J , Tinsley, J M ; Utterback, B G., Yan, S-C.B.; Zhang, M J Med Chem., 1997, 40, 3489, Tucker, T J , Lumma, W C.; Lewis, S D.; Gardell, S.J ; Lucas, B.J.; Sisko, J.T.; Lynch, J.J.; Lyle, E.A ; Baskin, E.P , Woltmann, R.F.; Appleby, S.D., Chen, I-W ; Dancheck, K B ; Naylor-Olsen, A M ; Krueger, J.A ; Cooper, C.M.; Vacca, J.P. J Med Chem , 1997, 40, 3687.
10. 4. For some recent references see; Oh, Y.S., Yun, M ; Hwang, S Y.; Hong, S.; Shin, Y.; Lee, K.; Yoon, K.H.; Yoo, Y J.; Kim, D.S.; Lee, S.H.; Lee, Y.H.; Park, H.D.; Lee, C H.; Lee, S K ; Kim, S. Bioorg Med Chem Lett , 1998, 8, 631, Fevig, J.M ; Bunak, J ,Jr , Cacciola, J ; Alexander, R S ; Kettner, C A., Knabb, R.M.; Pruitt, J R ; Weber, P C., Wexler, R.R. Bioorg Med Chem Lett , 1998, 8, 301; Brady, S.F.; Stauffer, K.J.; Lumma, W.C ; Smith, G M.; Ramjit, H.G ; Lewis, S.D.; Lucas, B.J ; Gardell, S J.; Lyle, E A.; Appleby, S.D , Cook, J.J , Holahan, M A ; Strameri, M T., Lynch, J J , Jr ; Lin, J H ; Chen, I.W., Vastag, K., Naylor-Olsen, A M.; Vacca, J.P. J Med Chem., 1998, 41, 401 ; Feng, D-M., Gardell, S J., Lewis, S D , Bock, M.G.; Chen, Z., Freidinger, R.M., Naylor-Olsen, A.M.; 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, JP. J Med Chem., 1997, 40, 3726, Sall, D J , Bastian, J A., Briggs, S.L ; Buben, J.A.; Chirgadze, N Y., Clawson, D.K.; Denney, M.L ; Giera, D D., Gifford-Moore, D.S.; Harper, R.W , Hauser, K L ; Khlimkowski, V.J.; Kohn, T.J.; Lin, H-S.; McCowan, J.R., Palkowitz, A.D.; Smith, G.F., Takeuchi, K.; Thrasher, K J , Tinsley, J M ; Utterback, B G., Yan, S-C.B.; Zhang, M J Med Chem., 1997, 40, 3489, Tucker, T J , Lumma, W C.; Lewis, S D.; Gardell, S.J ; Lucas, B.J.; Sisko, J.T.; Lynch, J.J.; Lyle, E.A ; Baskin, E.P , Woltmann, R.F.; Appleby, S.D., Chen, I-W ; Dancheck, K B ; Naylor-Olsen, A M ; Krueger, J.A ; Cooper, C.M.; Vacca, J.P. J Med Chem , 1997, 40, 3687.
11. 5. For a reference debating this strategy for discovering non-peptide leads see: Rees, C.D. Ann Rep Med Chem , 1993, 59.
12. 4→E + I*
13. 7. Ourisson, G.; Crabbe, P ; Rodig, O Tetracyclic Triterpenes, Holden-Day, San Francisco, 1964, for a synthetic approach to euphane triterpenes see Kolaczkowski, W , Reusen, W J Org Chem , 1985, 50, 4766
14. 7. Ourisson, G.; Crabbe, P ; Rodig, O Tetracyclic Triterpenes, Holden-Day, San Francisco, 1964, for a synthetic approach to euphane triterpenes see Kolaczkowski, W , Reusen, W J Org Chem , 1985, 50, 4766
15. 8 For example see Chiang, C ; Chiang, F.C. Tetrahedron, 1973, 29, 1911, Chiang, C., Chiang, F C. Tetrahedron Letters, 1969, 11, 891, Ma, K.W ; Chiang, F.C ; Clardy, J.C. J Chem Soc Chem. Commun , 1971, 424, Ochi, M , Kotsuki, H.; Tokoroyama, T., Kubota,T. Bull Chem Soc Jpn., 1977, 50, 2499, Nakai, H.; Shiro, M. Acta Cryst., 1978, B34, 2063.
16. 8 For example see Chiang, C ; Chiang, F.C. Tetrahedron, 1973, 29, 1911, Chiang, C., Chiang, F C. Tetrahedron Letters, 1969, 11, 891, Ma, K.W ; Chiang, F.C ; Clardy, J.C. J Chem Soc Chem. Commun , 1971, 424, Ochi, M , Kotsuki, H.; Tokoroyama, T., Kubota,T. Bull Chem Soc Jpn., 1977, 50, 2499, Nakai, H.; Shiro, M. Acta Cryst., 1978, B34, 2063.
17. 8 For example see Chiang, C ; Chiang, F.C. Tetrahedron, 1973, 29, 1911, Chiang, C., Chiang, F C. Tetrahedron Letters, 1969, 11, 891, Ma, K.W ; Chiang, F.C ; Clardy, J.C. J Chem Soc Chem. Commun , 1971, 424, Ochi, M , Kotsuki, H.; Tokoroyama, T., Kubota,T. Bull Chem Soc Jpn., 1977, 50, 2499, Nakai, H.; Shiro, M. Acta Cryst., 1978, B34, 2063.
18. 8 For example see Chiang, C ; Chiang, F.C. Tetrahedron, 1973, 29, 1911, Chiang, C., Chiang, F C. Tetrahedron Letters, 1969, 11, 891, Ma, K.W ; Chiang, F.C ; Clardy, J.C. J Chem Soc Chem. Commun , 1971, 424, Ochi, M , Kotsuki, H.; Tokoroyama, T., Kubota,T. Bull Chem Soc Jpn., 1977, 50, 2499, Nakai, H.; Shiro, M. Acta Cryst., 1978, B34, 2063.
19. 8 For example see Chiang, C ; Chiang, F.C. Tetrahedron, 1973, 29, 1911, Chiang, C., Chiang, F C. Tetrahedron Letters, 1969, 11, 891, Ma, K.W ; Chiang, F.C ; Clardy, J.C. J Chem Soc Chem. Commun , 1971, 424, Ochi, M , Kotsuki, H.; Tokoroyama, T., Kubota,T. Bull Chem Soc Jpn., 1977, 50, 2499, Nakai, H.; Shiro, M. Acta Cryst., 1978, B34, 2063.
20. 9. For some recent uses of electrospray ionisation mass spectrometry (EI-MS) with serme proteases see; Knight, W B.; Swidereck, K.M.; Sakuma,T.; Calaycay, J.; Shively, J.E., Lee, T D.; Covey, T R.; Shushman, B., Green, B G.; Chabin, R., Shah, S.; Mumford, R.; Dickenson, T A., Griffen, P.R. Biochemistry, 1993, 32, 2031, Sall, J. S.; Kaiser Jnr., R. E. J Med Chem , 1993, 36, 2350, Mini review on EI-MS, Ashton, D S., Beddell, C. R.; Green, B. N.; Oliver, R. W A. FEBS Letters, 1994, 342, 1.
21. 9. For some recent uses of electrospray ionisation mass spectrometry (EI-MS) with serme proteases see; Knight, W B.; Swidereck, K.M.; Sakuma,T.; Calaycay, J.; Shively, J.E., Lee, T D.; Covey, T R.; Shushman, B., Green, B G.; Chabin, R., Shah, S.; Mumford, R.; Dickenson, T A., Griffen, P.R. Biochemistry, 1993, 32, 2031, Sall, J. S.; Kaiser Jnr., R. E. J Med Chem , 1993, 36, 2350, Mini review on EI-MS, Ashton, D S., Beddell, C. R.; Green, B. N.; Oliver, R. W A. FEBS Letters, 1994, 342, 1.
22. 9. For some recent uses of electrospray ionisation mass spectrometry (EI-MS) with serme proteases see; Knight, W B.; Swidereck, K.M.; Sakuma,T.; Calaycay, J.; Shively, J.E., Lee, T D.; Covey, T R.; Shushman, B., Green, B G.; Chabin, R., Shah, S.; Mumford, R.; Dickenson, T A., Griffen, P.R. Biochemistry, 1993, 32, 2031, Sall, J. S.; Kaiser Jnr., R. E. J Med Chem , 1993, 36, 2350, Mini review on EI-MS, Ashton, D S., Beddell, C. R.; Green, B. N.; Oliver, R. W A. FEBS Letters, 1994, 342, 1.
23. 10 For other acylating inhibitors see reference 1, Powers, J C ; Harper, J.W. Inhibitors of serine proteinases, pg. 55-152.
24. 11. A detailed analysis of the X-ray structures of thrombin inhibited with GR133686 and 7 will be published in due course
25. 12 In press; Kelly, H.A.; Bolton, R , Brown, S.A., Coote, S.J., Dowle, M , Dyer, U , Finch, H , Golding, D , Lowdon, A.; McLaren, I, Montana, J.G ; Owen, M R., Pegg, N.A.; Ross, B.C., Thomas, R , Walker, D.A Tetrahedron Letters, n.b all the synthetic compounds described are racemic and possess satisfactory spectroscopic and / or analytical data.
26. 50 is the concentration of compound required to inhibit 50% of the enzyme-catalysed hydrolysis of the chromogenic substrate, the compounds being incubated with the enzyme for 15 mins, prior to substrate addition. Chymotrypsin substrate. Suc.Ala.Ala Pro.Phe-pNA. Human leucocyte elastase substrate: MeOSuc Ala Ala.Pro.Val.-pNA, Thrombin substrate: Tos.Gly.Pro.Lys.pNA. Trypsin and FXa substrate: S2222, Reported values are the mean of triplicate determinations
27. 14. Singh, O., Wonacott, A ; Jhoti, H. Unpublished work.
28. 15. For a recent commentary on factors that affect the potency of suicide enzyme inhibitors see; Ternansky, R.J., Draheim, S.E J. Med Chem , 1993, 36, 3219.
29. 2,-78°, α-isomer 0 5%, β-isomer 2%
30. 17. A recent paper from the Merck laboratories describes a potent thrombin inhibitor with a highly optimised, non-basic P-1 sidecham; Lumma Jr., W.C.; 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 J Med Chem., 1998, 41, 1011.
31. 18 Bolton, R E.; Coote, S.J.; Finch, H.; Lowdon, A ; Pegg, N ; Vinader, M V. Tetrahedron Letters, 1995, 16, 4471
32. 60f from the thrombin 'sixties loop'. It was not possible to establish the absolute configuration of the bound inhibitor from the X-ray data
33. 20 Grundke, G., Keese, W., Rimpler, M ; Chem Ber., 1985, 118, 4288.