&bgr;-sheet mimetics and use thereof as protease inhibitors

Details &bgr;-sheet mimetics and use thereof as protease inhibitors &bgr;-sheet mimetics and use thereof as protease inhibitors

1999-11-18

2003-07-01

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S228800, C514S359000, C514S368000, C514S369000, C514S413000, C514S464000, C514S221000, C514S562000, C514S222200, C562S560000

Reexamination Certificate

active

06586426

ABSTRACT:

TECHNICAL FIELD
This invention relates generally to &bgr;-sheet mimetics and, more specifically, to &bgr;-sheet mimetics for use as protease inhibitors.
BACKGROUND OF THE INVENTION
The &bgr;-sheet conformation (also referred to as a &bgr;-strand conformation) is a secondary structure present in many polypeptides. The &bgr;-sheet conformation is nearly fully extended, with axial distances between adjacent amino acids of approximately 3.5 Å. The &bgr;-sheet is stabilized by hydrogen bonds between NH and CO groups in different polypeptides strands. Additionally, the dipoles of the peptide bonds alternate among the strands which imparts intrinsic stability to the &bgr;-sheet. The adjacent strands in the &bgr;-sheet can run in the same direction (i.e., a parallel &bgr;-sheet) or in opposite directions (i.e., an antiparallel &bgr;-sheet). Although the two forms differ slightly in dihedral angles, both are sterically favorable. The extended conformation of the &bgr;-sheet conformation results in the amino acid side chains protruding on alternating faces of the &bgr;-sheet.
The importance of &bgr;-sheets in peptides and proteins is well established (e.g., Richardson,
Nature
268:495-499, 1977; Halverson et al.,
J. Am. Chem Soc
. 113:6701-6704, 1991; Zhang,
J. Biol. Chem
. 266:15591-15596, 1991; Madden et al.,
Nature
353:321-325, 1991). The &bgr;-sheet is important in a number of biological recognition events, including the interaction between proteases and proteolytic substrates. Protease activity has been implicated in many disease states.
Cathepsin B is a lysosomal cysteine protease normally involved in proenzyme processing and protein turnover. Elevated levels of activity have been implicated in tumor metastasis (Sloane, B. et al., “Cathepsin B and its endogenous inhibitors: the role in tumor malignancy,”
Cancer Metastasis Rev
. 9:333-352, 1990), rheumatoid arthritis (Werb, Z. “Proteinases and matrix degradation,” in Textbook of Rheumatology, Keller, W. N.; Harris, W. D.; Ruddy, S.; Sledge, C. S., Eds., 1989, W. B. Saunder Co., Philadelphia, Pa., pp. 300-321), and muscular dystrophy (Katunuma N. & Kominami E., “Abnormal expression of lysosomal cysteine proteinases in muscle wasting diseases,”
Rev. Physiol. Biochem. Pharmacol
. 108:1-20, 1987).
Calpains are cytosolic or membrane bound Ca++-activated proteases which are responsible for degradation of cytoskeletal proteins in response to changing calcium levels within the cell. They contribute to tissue degradation in arthritis and muscular dystrophy (see Wang K. K. & Yuen P. W., “Calpain inhibition: an overview of its therapeutic potential,”
Trends Pharmacol. Sci
. 15:412-419, 1994).
Interleukin Converting Enzyme (ICE) cleaves pro-IL-1 beta to IL-1 beta, a key mediator of inflammation, and therefore inhibitors or ICE may prove useful in the treatment of arthritis (see, e.g., Miller B. E. et al., “Inhibition of mature IL-1 beta production in murine macrophages and a murine model of inflammation by WIN 67694, an inhibitor of IL-1 beta converting enzyme,”
J. Immunol
. 154:1331-1338, 1995). ICE or ICE-like proteases may also function in apoptosis (programmed cell death) and therefore play roles in cancer, AIDS, Alzheimer's disease, and other diseases in which disregulated apoptosis is involved (see Barr, P. J.; Tomei, L. D., “Apoptosis and its Role in Human Disease,”
Biotechnol
. 12:487-493, 1994).
HIV protease plays a key role in the life cycle of HIV, the AIDS virus. In the final steps of viral maturation it cleaves polyprotein precursors to the functional enzymes and structural proteins of the virion core. HIV protease inhibitors were quickly identified as an excellent therapeutic target for AIDS (see Huff, J. R., “HIV protease: a novel chemotherapeutic target for AIDS,”
J. Med. Chem
. 34:2306-2314, and have already proven useful in its treatment as evidenced by the recent FDA approval of ritonavir, Crixivan, and saquinavir.
Angiotensin converting enzyme (ACE) is part of the renin-angiotensin system which plays a central role in the regulation of blood pressure. ACE cleaves angiotensin I to the octapeptide angiotensin II, a potent pressor agent due to its vasoconstrictor activity. Inhibition of ACE has proved therapeutically useful in the treatment or hypertension (Williams, G. H., “Converting-enzyme inhibitors in the treatment of hypertension,”
N. Engl. J. Med
. 319:1517-1525, 1989.
Collegenases cleave collagen, the major constituent of the extracellular matrix (e.g., connective tissue, skin, blood vessels). Elevated collagenase activity contributes to arthritis (Krane S. M. et al., “Mechanisms of matrix degradation in rheumatoid arthritis,”
Ann. N.Y. Acad. Sci
. 580:340-354, 1990.), tumor metastasis (Flug M. & Kopf-Maier P., “The basement membrane and its involvement in carcinoma cell invasion,”
Acta Anat. Basel
152:69-84, 1995), and other diseases involving the degradation of connective tissue.
Trypsin-like serine proteases form a large and highly selective family of enzymes involved in hemostasis/coagulation (Davie, E. W. and K. Fujikawa, “Basic mechanisms in blood coagulation,”
Ann. Rev
. 799-829, 1975) and complement activation (Muller-Eberhard, H. J., “Complement,”
Ann. Rev. Biochem
. 44:697-724, 1975). Sequencing of these proteases has shown the presence of a homologous trypsin-like core with amino acid insertions that modify specificity and which are generally responsible for interactions with other macromolecular components (Magnusson et al., “Proteolysis and Physiological Regulation,”
Miami winter Symposia
11:203-239, 976)
Thrombin, a trypsin-like serine protease, acts to provide limited preoloysis, both in the generation of fibrin from fibrinogen and the activation of the platelet receptor, and thus plays a critical role in thrombosis and hemostasis (Mann, K. G., “The assembly of blood clotting complexes on membranes,”
Trends Biochem. Sci
. 12:229-233, 1987). Thrombin exhibits remarkable specificity in the removal of fibrinopeptides A and B of fibrinogen through the selective cleavage of only two Arg-Gly bonds of the one-hundred and eighty-one Arg- or Lys-Xaa sequences in fibrinogen (Blomback, H.,
Blood Clotting Enzymology
, Seeger, W. H. (ed.), Academic Press, New York, 1967, pp. 143-215).
Many significant disease states are related to abnormal hemostasis, including acute coronary syndromes. Aspirin and heparin are widely used in the treatment of patients with acute coronary syndromes. However, these agents have several intrinsic limitations. For example, thrombosis complicating the rupture of atherosclerotic plaque tends to be a thrombin-mediated, platelet-dependent process that is relatively resistant to inhibition by aspirin and heparin (Fuster et al., “The pathogenesis of coronary artery disease and the acute coronary syndromes,”
N. Engl. J. Med
. 326:242-50, 1992).
Thrombin inhibitors prevent thrombus formation at sites of vascular injury in vivo. Furthermore, since thrombin is also a potent growth factor which initiates smooth muscle cell proliferation at sites of mechanical injury in the coronary artery, inhibitors block this proliferative smooth muscle cell response and reduce restenosis. Thrombin inhibitors would also induce the inflammatory response in vascular wall cells (Harker et al.,
Am. J. Cardiol
75:12B-16B, 1995).
In view of the important biological role played by the &bgr;-sheet, there is a need in the art for compounds which can stabilize the intrinsic &bgr;-sheet structure of a naturally occurring or synthetic peptide, protein or molecule. There is also a need in the art for making stable &bgr;-sheet structures, as well as the use of such stabilized structures to effect or modify biological recognition events which involve &bgr;-sheet structures. The present invention fulfills these needs and provides further related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention is directed to &bgr;-sheet mimetics and, more specifically, to &bgr;-sheet mimetics which stabilize the &bgr;-strand structure of a natural or synthetic peptide, protein

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