Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-05
1997-03-04
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544387, 544391, 544360, 544295, 544121, 544376, 544380, C07D295192, C07D40104, C07D40304, A61K 31495
Patent
active
056079370
DESCRIPTION:
BRIEF SUMMARY
This application is the national stage of PCT/CH94/00026, filed Feb. 9, 1994.
The present invention relates to new proteinase inhibitors which contain phenylalanine as the core structure, wherein the aromatic residue in meta position carries a basic group and the a-amino group is sulfonylated with various residues. The C-terminal introduction of different, N-substituted piperazine residues led to the discovery of highly efficient inhibitors showing improved bioavailability.
Proteinase inhibitors are potential drugs which can be used to control physiological processes induced and maintained by proteinases. For many endogenous and naturally occurring inhibitors, respectively, it has been shown that they can influence the activity of proteinases in vivo and alleviate hyperproteolytic states [see H orl, W. H. In: Design of Enzyme Inhibitors as Drugs, p. 573-581, (Sandler, M. and Smith, H. J., Eds.) Oxford, New York, Tokyo: Oxford University Press, 1989]. However, the therapeutic application of such inhibitors of relatively high molecular weight is limited due to their particular protein structure. As these inhibitors are not absorbed in the intestine upon oral administration on the one hand and exert an antigenic activity on the other hand, it was of great interest to search for synthetic enzyme inhibitors of low molecular weight.
The four classes of enzymes which are responsible for proteinase-dependent processes comprise the serine, thiol, metallo, and aspartate proteinases. Serine proteinases are proteolytic enzymes which possess a reactive serine residue in the active center. Enzymes which, such as trypsin, split off C-terminal peptide bonds of the basic amino acids arginine and lysine, belong to the trypsin family of the serine proteinases. In this group, those enzymes which induce coagulation and fibrinolysis in the blood, which release kinin and produce the complement activation or those which themselves are components of the mentioned enzyme systems, are of particular physiological significance.
Blood coagulation is triggered by zymogen activation via two different pathways. The first, intrinsic pathway leads to blood coagulation via a chain of reactions mediated by blood constituents. The second, extrinsic pathway leads to coagulation via a shorter chain of reactions based on an interaction between blood and tissue constituents. Both ways produce the activation of the zymogen factor X into the serine proteinase factor X.sub.a which itself catalyzes the activation of prothrombin into the fibrinogen-coagulating serine proteinase, thrombin. Being a common product of the intrinsic as well as of the extrinsic activation pathway, factor X.sub.a was initially considered to be the preferential target enzyme for inhibitory intervention in the blood coagulation process (Tidwell, R. R. et al., Thromb. Res. 19, 339-349, 1980). However, it has been recently demonstrated that synthetic inhibitors of factor X.sub.a in vitro and in vivo are not coagulation-inhibiting (St urzebecher, J. et al., Thromb. Res. 54, 245-252, 1989) and antithrombotically efficient (Hauptmann, J. et al., Thromb. Haemostas. 63, 220-223, 1990). Therefore, the development of anticoagulant inhibitors is focused on the discovery of thrombin inhibitors.
For the development of synthetic inhibitors for thrombin, benzamidine derivatives have been extensively investigated (St urzebecher, J. et al., Acta Biol. Med. Germ. 35, 1665-1676, 1976). Among them, amino acid derivatives containing a benzamidine moiety and a para-oriented amidino group proved to be favorable core structures for the development of effective inhibitors. Until now, the most efficient thrombin inhibitor of the benzamidine type described is the amino acid derivative N.alpha.-(2-naphthylsulfonyl)-glycyl-4-amidinophenylalanine piperidide (NAPAP) (K.sub.i =6.times.10 .sup.-9 mol/l ) (St urzebecher, J. et al., Thromb. Res. 29, 635-642, 1983).
Other types of inhibitors which also effectively inhibit thrombin are known: a first group is comprised of the peptidyl-arginine-chloromethyl ketone
Adler Christoph
Stuerzebecher Joerg
Vieweg Helmut
Wikstroem Peter
Pentapharm AG
Shah Mukund J.
Wong King Lit
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