Meta-substituted phenylalanine derivatives

Details Meta-substituted phenylalanine derivatives Meta-substituted phenylalanine derivatives

1993-02-10

1996-05-21

Venkat, Jyothsna

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

424435, 424436, 424451, 424464, 424489, 514255, 514307, 514316, 514327, 514423, 544386, 544391, 546145, 546189, 546206, 548532, 548533, 548535, 548536, 558 61, A61F 1304, C07C31300

Patent

active

055187358

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to new proteinase inhibitors which contain a phenylalanine residue which carries a substitution on its phenyl ring. Variation of the substituent on the phenyl ring and in particular the introduction of hydrophobically substituted secondary amino acids led to the discovery of 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 Horl, 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 participate in the defense systems of blood are of particular physiological significance. Particularly, they are the enzymes of the coagulation system, but also those which induce fibrinolysis, release kinin and produce the complement activation or those which themselves are components of the mentioned enzyme systems.
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 appears to be a preferential target enzyme for inhibitory intervention in the blood coagulation process.
For the development of synthetic inhibitors for trypsin-like serine proteinases, benzamidine derivatives have been extensively investigated (J. Sturzebecher et al., Acta Biol. Med. Germ. 35, 1665-1676, 1976). Among them, amino acid derivatives containing a benzamidine moiety proved to be particularly favorable core structures (G. Wagner et al., Pharmazie 56, 597-603, 1981 and J. Sturzebecher et al., ibid, 639-641; UK Patent Application 2 007 663 A). Among these compounds, phenylalanine derivatives with a meta-oriented amidino group are selective factor X.sub.a inhibitors while analogous compounds with a para-oriented amidino group are the core structures for the development of selective thrombin inhibitors.
N.alpha.-tosylglycyl-3-amidinophenylalanine methyl ester (TAPAM; K.sub.i =8.4.times.10.sup.-7 mole/l) has been proposed as a selective factor X.sub.a -inhibiting amino acid derivative containing a benzamidine moiety and a meta-oriented amidino group (J. Sturzebecher et al., Thromb. Res. 54, 245-252, 1989). The most efficient thrombin inhibitor is the phenylalanine derivative N.alpha.-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide (K.sub.i =6.times.10.sup.-9 mole/l) with a para-oriented amidino group which is designated as NAPAP (J. Sturzebecher et al., Thromb. Res. 29, 635-642, 1983)

REFERENCES:
patent: 4125604 (1978-11-01), Okamoto et al.
G. Wagner et al., Die Pharmazie, 36, No. 9, Sep., 1981, pp. 597-603.
J. Sturzebecker et al., Die Pharmazie, vol. 36, No. 9, Sep. 1981, pp. 639-641.
J. Sturzebecker et al., Thrombosis Research, vol. 54, No. 3, May 15, 1989, pp. 245-252.
H. Vieweg et al., Die Pharmazie, vol. 42, No. 4, Apr. 1987, p. 268.
J. Hauptmann et al., Thrombosis and Haemostasis, vol. 63, No. 2, Apr. 12, 1990, pp. 220-223.
Chemical Abstracts No. 40333V, vol. 107, No. 5, Aug. 3, 1987.
Chemical Abstracts No. 107770B, vol. 98, No. 13, Mar. 28, 1983.

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