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Brady SF, Sisko JT, Stauffer KJ, Colton CD, Qiu H, Lewis SD, Ng AS, Shafer JA, Bogusky MJ, Veber DF, Nutt RF: Amide and α-keto carbonyl inhibitors of thrombin based on arginine and lysine: synthesis, stability and biological characterization. Bioorg Med Chem 1995, 3:1063-1078.
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Lewis, S.D.6
Ng, A.S.7
Shafer, J.A.8
Bogusky, M.J.9
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Nutt, R.F.11
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39
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Kinetic and crystallographic studies of thrombin with Ac-(D)Phe-Pro-boroArg-OH and its lysine, amidine, homolysine and orthithine analogs
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Weber PC, Lee S-L, Lewandowski FA, Schadt MC, Chang C-H, Kettner CA: Kinetic and crystallographic studies of thrombin with Ac-(D)Phe-Pro-boroArg-OH and its lysine, amidine, homolysine and orthithine analogs. Biochemistry 1995, 34:3750-3757.
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Biochemistry
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Schadt, M.C.4
Chang, C.-H.5
Kettner, C.A.6
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40
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0030783589
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New inhibitors of thrombin and other trypsin-like proteases: Hydrogen bonding of an aromatic cyano group with a backbone amide of the P1 binding site replaces binding of a basic side chain
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Lee S-L, Alexander RS, Smallwood A, Trievel R, Mersinger L, Weber PC, Kettner C: New inhibitors of thrombin and other trypsin-like proteases: hydrogen bonding of an aromatic cyano group with a backbone amide of the P1 binding site replaces binding of a basic side chain. Biochemistry 1997, 36:13180-13186. This paper describes an interesting approach for enhancing the potency of thrombin inhibitors with a neutral P1 group.
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Biochemistry
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Lee, S.-L.1
Alexander, R.S.2
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Kettner, C.7
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41
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Bioavailability of a novel, direct thrombin inhibitor in non-human primates following oral administration
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Richard BM, Nolan TG, Tran HS, Miller MM, Nutt RF, Vlasuk GP: Bioavailability of a novel, direct thrombin inhibitor in non-human primates following oral administration. Circulation 1994, 90:1-18.
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Vlasuk, G.P.6
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42
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Design of highly potent noncovalent thrombin inhibitors that utilize a novel lipophilic binding pocket in the thrombin active site
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Tucker TJ, Lumma WC, Mulichak AM, Chen Z, Naylor-Olsen AM, Lewis SD, Lucas R, Freidinger RM, Kuo LC: Design of highly potent noncovalent thrombin inhibitors that utilize a novel lipophilic binding pocket in the thrombin active site. J Med Chem 1997, 40:830-832. This paper exemplifies the application of structure/activity studies to identify unusually potent inhibitors.
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Lewis, S.D.6
Lucas, R.7
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Kuo, L.C.9
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Potent noncovalent thrombin inhibitors that utilize the unique amino acid D-dicyclohexylalanine in the P3 position. Implications on oral bioavailability and antithrombotic efficacy
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Tucker TJ, Lumma WC, Lewis SD, Gardell SJ, Lucas BJ, Baskin EP, Weltmann R, Lynch JJ, Lyle EA, Appleby SD et al.: Potent noncovalent thrombin inhibitors that utilize the unique amino acid D-dicyclohexylalanine in the P3 position. Implications on oral bioavailability and antithrombotic efficacy. J Med Chem 1997, 40:1565-1569.
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Tucker, T.J.1
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Lewis, S.D.3
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Baskin, E.P.6
Weltmann, R.7
Lynch, J.J.8
Lyle, E.A.9
Appleby, S.D.10
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44
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Synthesis of a series of potent and orally bioavailable thrombin inhibitors that utilize 3,3-disubstituted propionic acid derivatives in the P3 position
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Tucker TJ, Lumma WC, Lewis SD, Gardell SJ, Lucas BJ, Sisko JT, Lynch JJ, Lyle EA, Baskin EP, Weltmann RF et al.: Synthesis of a series of potent and orally bioavailable thrombin inhibitors that utilize 3,3-disubstituted propionic acid derivatives in the P3 position. J Med Chem 1997, 40:3687-3693. This paper exemplifies optimization of lipophilicity to achieve oral bioavailability and in vivo anticoagulant potency.
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J Med Chem
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Tucker, T.J.1
Lumma, W.C.2
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Lynch, J.J.7
Lyle, E.A.8
Baskin, E.P.9
Weltmann, R.F.10
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45
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Discovery and development of the novel potent orally active thrombin inhibitor N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460): Coapplication of structure-based design and rapid multiple analogue synthesis on solid support
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Brady SF, Stauffer KJ, Lumma WC, Smith GM, Ramjit HG, Lewis SD, Lucas BJ, Gardell SJ, Lyle EA, Appleby SD et al.: Discovery and development of the novel potent orally active thrombin inhibitor N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460): coapplication of structure-based design and rapid multiple analogue synthesis on solid support. J Med Chem 1998, 41:401-406.
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J Med Chem
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Brady, S.F.1
Stauffer, K.J.2
Lumma, W.C.3
Smith, G.M.4
Ramjit, H.G.5
Lewis, S.D.6
Lucas, B.J.7
Gardell, S.J.8
Lyle, E.A.9
Appleby, S.D.10
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46
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Discovery of a novel, selective and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position
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Feng D-M, Gardell SJ, Lewis SD, Bock MG, Chen Z, Freidinger RM, Naylor-Olsen AM, Ramjit HG, Woltmann R, Baskin EP et al.: 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.
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J Med Chem
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Feng, D.-M.1
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Ramjit, H.G.8
Woltmann, R.9
Baskin, E.P.10
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47
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L-374,087, an efficacious orally bioavailable, pyridinone acetamide thrombin inhibitor
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Sanderson PEJ, Cutrona KJ, Dorsey BD, Dyer DL, McDonough CM, Naylor-Olsen AM, Chen I-W, Chen Z, Cook JJ, Gardell SJ et al.: L-374,087, an efficacious orally bioavailable, pyridinone acetamide thrombin inhibitor. Bioorg Med Chem Letts 1998, 8:817-822. This paper illustrates how alteration of the basicity of a thrombin inhibitor can increase oral bioavailability.
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Bioorg Med Chem Letts
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Sanderson, P.E.J.1
Cutrona, K.J.2
Dorsey, B.D.3
Dyer, D.L.4
McDonough, C.M.5
Naylor-Olsen, A.M.6
Chen, I.-W.7
Chen, Z.8
Cook, J.J.9
Gardell, S.J.10
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48
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Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes
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Gustafsson D, Antonsson T, Bylund R, Eriksson U, Gyzander E, Nilsson I, Elg M, Mattsson C, Deinum J, Pehrsson S et al.: Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998, 79:110-118.
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Eriksson, U.4
Gyzander, E.5
Nilsson, I.6
Elg, M.7
Mattsson, C.8
Deinum, J.9
Pehrsson, S.10
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49
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The importance of enzyme inhibition kinetics for thrombin inhibitors in a rat model of arterial thrombosis
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Elg M, Gustafsson D, Deinum J: The importance of enzyme inhibition kinetics for thrombin inhibitors in a rat model of arterial thrombosis. Thromb Haemost 1997, 78:1286-1292.
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Discovery of LB30057, a benzamidrazone-based selective oral thrombin inhibitor
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Oh YS, Yun M, Hwang SY, Hong S, Shin Y, Lee K, Yoon KH, Yoo YJ, Kim DS, Lee SH et al.: Discovery of LB30057, a benzamidrazone-based selective oral thrombin inhibitor. Bioorg Med Chem Lett 1998, 8:631-634.
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Oh, Y.S.1
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Shin, Y.5
Lee, K.6
Yoon, K.H.7
Yoo, Y.J.8
Kim, D.S.9
Lee, S.H.10
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The discovery of UK-156,406-an orally active thrombin inhibitor
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Washington, DC: American Chemical Society
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Allen M, Abel SM, Barber CG, Cussans NJ, Danielewicz JC, Ellis D, Hawkeswood E, Herron M, Holland S, Fox DNA et al.: The discovery of UK-156,406-an orally active thrombin inhibitor. Book of abstracts. 215th American Chemical Society National Meeting, Dallas, March 29-April 2 1998; Washington, DC: American Chemical Society; 1998:A200.
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Book of Abstracts. 215th American Chemical Society National Meeting, Dallas, March 29-April 2 1998
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Allen, M.1
Abel, S.M.2
Barber, C.G.3
Cussans, N.J.4
Danielewicz, J.C.5
Ellis, D.6
Hawkeswood, E.7
Herron, M.8
Holland, S.9
Fox, D.N.A.10
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52
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0030768740
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Synthesis and structure - Activity relationships of potent thrombin inhibitors: Piperazides of 3-amidinophenylalanine
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Stürzebecher J, Prasa D, Hauptmann J, Vieweg H, Wikström P: Synthesis and structure - activity relationships of potent thrombin inhibitors: piperazides of 3-amidinophenylalanine. J Med Chem 1997, 40:3091-3099.
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J Med Chem
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Stürzebecher, J.1
Prasa, D.2
Hauptmann, J.3
Vieweg, H.4
Wikström, P.5
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53
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0030835791
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The crystal structure of human α-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor
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Chirgadze NY, Sall DJ, Klimkowski VJ, Clawson DK, Briggs SL, Herman R, Smith GF, Gifford-Moore DS, Wery J-P: The crystal structure of human α-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor. Protein Sci 1997, 6:1412-1417. This paper characterizes the interactions of thrombin with a new class of amidinoindole nonpeptidyl thrombin inhibitors.
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Protein Sci
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Chirgadze, N.Y.1
Sall, D.J.2
Klimkowski, V.J.3
Clawson, D.K.4
Briggs, S.L.5
Herman, R.6
Smith, G.F.7
Gifford-Moore, D.S.8
Wery, J.-P.9
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54
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Dibasic benzo[b]thiophene derivatives as a novel class of active site-directed thrombin inhibitors. 1. Determination of the serine protease selectivity, structure-activity relationships, and binding orientation
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Sail DJ, Bastian JA, Briggs SL, Buben JA, Chirgadze NY, lawson DK, Denney ML, Giera DD, Gifford-Moore DS, Harper RW et al.: Dibasic benzo[b]thiophene derivatives as a novel class of active site-directed thrombin inhibitors. 1. Determination of the serine protease selectivity, structure-activity relationships, and binding orientation. J Med Chem 1997, 40:3489-3493. This paper characterizes the interactions of thrombin with a novel class of dibasic benzothiophene nonpeptidyl inhibitors.
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J Med Chem
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Sail, D.J.1
Bastian, J.A.2
Briggs, S.L.3
Buben, J.A.4
Chirgadze, N.Y.5
Clawson, D.K.6
Denney, M.L.7
Giera, D.D.8
Gifford-Moore, D.S.9
Harper, R.W.10
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Dibasic benzo(b)thiophene derivatives as a novel class of thrombin inhibitors. 3. Optimization of the C-3 sidechain
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Washington, DC: American Chemical Society
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Sail DJ, Bastian JA, Chirgadze NY, Denney ML, Gifford-Moore DS, Harper TRW, Kohn TJ, Lin H-S, McCowan JR, Richett ME et al.: Dibasic benzo(b)thiophene derivatives as a novel class of thrombin inhibitors. 3. Optimization of the C-3 sidechain. Book of abstracts. 214th American Chemical Society National Meeting, Las Vegas, September 7-11 1997; Washington, DC: American Chemical Society; 1998:A57.
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Book of Abstracts. 214th American Chemical Society National Meeting, Las Vegas, September 7-11 1997
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Sail, D.J.1
Bastian, J.A.2
Chirgadze, N.Y.3
Denney, M.L.4
Gifford-Moore, D.S.5
Harper, T.R.W.6
Kohn, T.J.7
Lin, H.-S.8
McCowan, J.R.9
Richett, M.E.10
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56
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Molecular recognition at the thrombin active site: Structure-based design and synthesis of potent and selective thrombin inhibitors and the X-ray crystal structures of two thrombin-inhibitor complexes
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Obst U, Banner DW, Weber L, Diederich F: Molecular recognition at the thrombin active site: structure-based design and synthesis of potent and selective thrombin inhibitors and the X-ray crystal structures of two thrombin-inhibitor complexes. Chem Biol 1997, 4:287-295. Rigid bicyclic and tricyclic nonpeptidyl thrombin inhibitors are characterized in this study.
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Chem Biol
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Obst, U.1
Banner, D.W.2
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Wiley MR, Fisher MJ: Small-molecule direct thrombin inhibitors. Exp Opin Ther Patents 1997, 7:1265-1282.
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Exp Opin Ther Patents
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Wiley, M.R.1
Fisher, M.J.2
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Al-Obeidi F, Ostrem JA: Factor Xa inhibitors by classical and combinatorial chemistry. Drug Discov Today 1998, 3:223-231.
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X-ray structure of active site-inhibited clotting factor Xa
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Brandstetter H, Kühne A, Bode W, Hubert R, von der Saal W, Wirthensohn K, Engh RA: X-ray structure of active site-inhibited clotting factor Xa. J Biol Chem 1996, 271:29988-29992.
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