Thrombin inhibitors, the preparation thereof and the use thereof

Details Thrombin inhibitors, the preparation thereof and the use thereof Thrombin inhibitors, the preparation thereof and the use thereof

1995-10-16

1998-03-03

Tsang, Cecilia J.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

25 or more amino acid residues in defined sequence

514 12, 424 169, C07K 1400, A61K 3816

Patent

active

057235767

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to thrombin inhibitors, the preparation thereof and the use thereof for therapeutical, prophylactic and diagnostic applications.
Thrombin is a serin-protease involved in various important physiological Shavit, R. and Wilner, G. D. (1986) Int. Rev. Exp. Pathol., 29, 213-241!.
Besides playing a role in blood coagulation, thrombin also has other activities, among which a strong mitogenic signal with fibroblasts in vitro, and it also exerts a chemotactic effect on monocytes (Bar Shavit). R. M. et al. (1984), J. Biol. Chem., 259, 9078-9081; Snider, R. M. (1986), Ann. N.Y. Acad. Sci., 485, 310-313!: it is involved in the control of Natl. Acad. Sci., 85, 3440-3444!.
Thrombin seems to also have a role in promoting cancer, due to the capability of fibrin, which is its digestion product, to act as a 5558-67; Gordon, S. G. et al. (1985), Blood, 66, 1261-65; Falanga A. et al., (1988), Blood, 71, 870-75!.
Many pathologies being a high risk for health, such as cardiac infarction, thrombosis, peripheral arteries occlusions, and the like, require a regulation of thrombin activity.
The physiological inhibitor of thrombin in blood is antithrombin III, but Fed. Am. Soc. Exp. Biol., 36, 10-18!. Heparin increases thrombin (1982), J. Biol. Chem., 257, 14891-14895!, therefore it is commonly used as a therapeutical agent, e.g. in venous thromboembolism, in which thrombin activity is responsible for the development or the expansion of a thrombus.
However, the use of heparin has some drawbacks: it is ineffective in patients lacking antithrombin III and it has a short half-life in blood; it fails to interrupt platelet-mediated arterial thrombosis or the Invest., 65, 64-73; Hanson, R. S. and Harker, L. A. (1988), Proc. Natl. Acad. Sci., USA, 85, 3184-3188!. Due to these and other drawbacks, a search for different compounds useful for a fast inactivation of thrombin has been required.
Hirudin, a polypeptide of molecular weight 6950 excreted by the salivary glands of Hirudo medicinalis, belongs to a family of polypeptides containing about 65 single chain amino acids (a.a.) and it is a strong Konno, S., et al., G. B. 1988, Arch. Bioch. Biophys. 267, 158-166; Fenton J. W. et al. (1988), Biochemistry, 27, 7106-7112; Stone, S. R. et al. (1986), Biochemistry, 25, 4622-4628!. Hirudin binds to thrombin (K.sub.i =6.3.times.10.sup.-11 M) forming a non covalent complex 1:1; such an interaction occurs at a different site from the enzyme catalytic site, even though hirudin additionally also binds to the active site. Therefore, in hirudin itself, three different domains can be evidenced: i) the N-terminal segment penetrating into thrombin catalytic site; ii) the C-terminal segment, of about 18 residues, which binds in a mainly cationic groove of thrombin; iii) the central nucleus (residues 5-48) acting as a spacer of the two N- and C-terminal domains.
Hirudin has successfully been used as an anticoagulant and antithrombotic agent. Contrary to heparin, hirudin require s no presence of endogenous cofactors such as antithrombin III and it is not bound or inactivated by platelet factors or by other substances having antiheparin effects. Hirudin differs from heparin in that it causes no bleeding side-effects.
Notwithstanding said advantages and even though hirudin is nowadays 21, Suppl. 1, 11-26!, the clinical use of hirudin is restricted mainly since the substance is not available in sufficient amounts for therapeutical purposes.
Therefore a number of researchers are involved efforts to synthesize hirudin peptide fragments which are easier and less expensive to prepare and have an antithrombotic activity similar or even higher than that of hirudin.
Compounds inhibiting thrombin are known in literature and among them WO-9119734; GB-2242681; EP-443598; EP-443429; EP-421367; WO-9101328; WO-9101142; EP-372670; EP-372503; EP-364942; EP-341607; 9049 U.S. Pat. No. 4,971,953; EP-333356; EP-291982; EP-276014; WO-9102750; J. M. Maraganore, et al., Biochemistry, (1990), 29, 70957101; J. M. Maraganore, et al., J. Biol. Chem., (1989),

REFERENCES:
patent: 5256559 (1993-10-01), Maraganore et al.
Maraganore et al., "Design and Characterization of Hiulogs: A novel class of Bivalent Peptide Inhibitors of Thrombin", Biochemistry, vol. 29, pp. 7095-7101, 1990.
Szewczuk et al, "Desing of a Linker for Trivalent Thrombin Inhibitors: Interaction of the Main Chain of the Linker with Thrombin", Biochemistry, vol. 32, pp. 3396-3404, 1993.

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