Ebook: The Design of Synthetic Inhibitors of Thrombin

In one generation, the numerous factors involved in blood coagulation have become real protein entities, isolated in pure form, expressed by recombinant DNA techniques, and subjected to structure elucidation by the modem methods of physical chemistry, viz. , X-ray diffraction, and NMR, ESR and fluorescence spectroscopy. The major milestone in this field was the breakthrough achieved by W. Bode, R. Huber and their colleagues in 1989 in of human a-thrombin, inhibited with D-Phe-Pro-Arg determining the crystal structure chioromethyl ketone. The availability of this structure will greatly facilitate the interpretation of experiments designed to gain an understanding of the interatomic interactions between this enzyme and fibrinogen and its other substrates. At the same time, it provides a rational basis for the design and synthesis of inhibitors of thrombin, the subject of this symposium. The symposium was organized in four sessions: (1) Structural features of the interaction of thrombin with substrates and inhibitors, (2) Synthetic inhibitors, (3) Hirudin and its analogues, and (4) Pharmacological and clinical considerations. This book contains summaries of most of the papers presented, and takes its rigbful place among two others that provide a comprehensive picture of our current knowledge about thrombin, viz. the 1977 volume entitled "Chemistry and Biology of Thrombin", edited by R. L. Lundblad, J. W. Fenton II, and K. G. Mann, and the 1992 volume entitled "Thrombin: Structure and Function", edited by L. J. Berliner.

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Content:
Front Matter....Pages i-x
The Rational Design of Thrombin-Directed Antithrombotics....Pages 1-13
X-Ray Crystal Structures of Thrombin in Complex with D-Phe-Pro-Arg and with Small Benzamidine- and Arginine-Based “Non-Peptidic” Inhibitors....Pages 15-26
Inhibitor Binding to Thrombin: X-Ray Crystallographic Studies....Pages 27-33
Molecular Basis for the Inhibition of Thrombin by Hirudin....Pages 35-49
Biophysical Studies of Interactions of Hirudin Analogs with Bovine and Human Thrombin by ESR and Fluorescence Labelling Studies....Pages 51-65
pH-Dependent Binding Constants for the Inhibition of Thrombin by Transition State Analogs....Pages 67-77
The Comparison of an Interim Tertiary Predicted Model of Bovine Thrombin and the X-Ray Structure of Human Thrombin....Pages 79-81
Design of Novel Types of Thrombin Inhibitors Based on Modified D-Phe-Pro-Arg Sequences....Pages 83-89
Chemistry and Biology of the Peptide Anticoagulant D-MePhe-Pro-Arg-H (GYKI-14766)....Pages 91-108
Peptide Boronic Acid Inhibitors of Thrombin....Pages 109-118
The Use of Isosteric Bonds in the Design of Thrombin Inhibitors....Pages 119-130
Synthetic Thrombin Inhibitors as Anticoagulants Pharmacological Aspects....Pages 131-141
New Peptide Boronic Acid Inhibitors of Thrombin....Pages 143-171
Substrate-Related Phosphonopeptides as Thrombin Inhibitors....Pages 173-178
The Synthesis and Anticoagulant Activity of Novel Peptidylfluoroalkanes....Pages 179-184
Transition State Analogue Inhibitors of Thrombin: Synthesis, Activity and Molecular Modelling....Pages 185-188
Hirudin: The Famous Anticoagulant Agent....Pages 189-190
Mechanisms for the Anticoagulant Effects of Synthetic Antithrombins....Pages 191-211
Pre-Clinical and Clinical Studies on Hirulog: A Potent and Specific Direct Thrombin Inhibitor....Pages 213-226
Back Matter....Pages 227-236
The Effect of Recombinant Hirudin on Arterial Thrombosis....Pages 243-246
....Pages 237-241