Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
1999-10-29
2002-07-16
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C514S018700, C514S019300, C548S100000, C562S571000
Reexamination Certificate
active
06420522
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel classes of compounds which are inhibitors of interleukin-1&bgr; converting enzyme (“ICE”). The ICE inhibitors of this invention are characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting ICE activity and consequently, may be advantageously used as agents against interleukin-1 (“IL-1”) mediated diseases, including inflammatory diseases, autoimmune diseases and neurodegenerative diseases. This invention also relates to methods for inhibiting ICE activity and methods for treating interleukin-1 mediated diseases using the compounds and compositions of this invention.
BACKGROUND OF THE INVENTION
Interleukin 1 (“IL-1”) is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. Oppenheim, J. H. et al,
Immunology Today,
7, pp. 45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. IL-1 is predominantly produced by peripheral blood monocytes as part of the inflammatory response and exists in two distinct agonist forms, IL-1&agr; and IL-1&bgr;. Mosely, B. S. et al.,
Proc. Nat. Acad. Sci.,
84, pp. 4572-4576 (1987); Lonnemann, G. et al.,
Eur. J. Immunol.,
19, pp. 1531-1536 (1989).
IL-1&bgr; is synthesized as a biologically inactive precursor, pIL-1&bgr;. pIL-1&bgr; lacks a conventional leader sequence and is not processed by a signal peptidase. March, C. J.,
Nature,
315, pp. 641-647 (1985). Instead, pIL-1&bgr; is cleaved by interleukin-1&bgr; converting enzyme (“ICE”) between Asp-116 and Ala-117 to produce the biologically active C-terminal fragment found in human serum and synovial fluid. Sleath, P. R., et al.,
J. Biol. Chem.,
265, pp. 14526-14528 (1992); A. D. Howard et al.,
J. Immunol.,
147, pp. 2964-2969 (1991). Processing by ICE is also necessary for the transport of mature IL-1&bgr; through the cell membrane.
ICE is a cysteine protease localized primarily in monocytes. It converts precursor IL-1&bgr; to the mature form. Black, R. A. et al.,
FEBS Lett.,
247, pp. 386-390 (1989); Kostura, M. J. et al.,
Proc. Natl. Acad. Sci. USA,
86, pp. 5227-5231 (1989). ICE, or its homologues, also appears to be involved in the regulation of cell death or apoptosis. Yuan, J. et al.,
Cell,
75, pp. 641-652 (1993); Miura, M. et al.,
Cell,
75, pp. 653-660 (1993); Nett-Fiordalisi, M. A. et al.,
J. Cell Biochem.,
17B, p. 117 (1993). In particular, ICE or ICE homologues are thought to be associated with the regulation of apoptosis in neurogenerative diseases, such as Alzheimer's and Parkinson's disease. Marx, J. and M. Baringa,
Science,
259, pp. 760-762 (1993); Gagliardini, V. et al.,
Science,
263, pp. 826-828 (1994).
ICE has been previously described as a heterodimer composed of two subunits, p20 and p10 (20 kDa and 10 kDa molecular weight, respectively). These subunits are derived from a 45 kDa proenzyme (p45) by way of a p30 form, through an activation mechanism that is autocatalytic. Thornberry, N. A. et al.,
Nature,
356, pp. 768-774 (1992). The ICE proenzyme has been divided into several functional domains: a prodomain (p14), a p22/20 subunit, a polypeptide linker and a p10 subunit. Thornberry et al., supra; Casano et al.,
Genomics,
20, pp. 474-481 (1994).
Full length p45 has been characterized by its cDNA and amino acid sequences. PCT patent applications WO 91/15577 and WO 94/00154. The p20 and p10 cDNA and amino acid sequences are also known. Thornberry et al., supra. Murine and rat ICE have also been sequenced and cloned. They have high amino acid and nucleic acid sequence homology to human ICE. Miller, D. K. et al.,
Ann. N.Y. Acad. Sci.,
696, pp. 133-148 (1993); Molineaux, S. M. et al.,
Proc. Nat. Acad. Sci.,
90, pp. 1809-1813 (1993). Knowledge of the primary structure of ICE, however, does not allow prediction of its tertiary structure. Nor does it afford an understanding of the structural, conformational and chemical interactions of ICE and its substrate pIL-1&bgr; or other substrates or inhibitors.
ICE inhibitors represent a class of compounds useful for the control of inflammation or apoptosis or both. Peptide and peptidyl inhibitors of ICE have been described. PCT patent applications WO 91/15577; WO 93/05071; WO 93/09135; WO 93/14777 and WO 93/16710; and European patent application 0 547 699. However, due to their peptidic nature, such inhibitors are typically characterized by undesirable pharmacologic properties, such as poor oral absorption, poor stability and rapid metabolism. Plattner, J. J. and D. W. Norbeck, in
Drug Discovery Technologies,
C. R. Clark and W. H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126. This has hampered their development into effective drugs.
Accordingly, the need exists for compounds that can effectively inhibit the action of ICE, for use as agents for preventing and treating chronic and acute forms of IL-1 mediated diseases, including various cancers, as well as inflammatory, autoimmune or neurodegenerative diseases.
SUMMARY OF THE INVENTION
The present invention provides novel classes of compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of ICE. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as antibiotics, immunomodulators or other anti-inflammatory agents, for the treatment or prophylaxis of diseases mediated by IL-1. According to a preferred embodiment, the compounds of this invention are capable of binding to the active site of ICE and inhibiting the activity of that enzyme.
It is a principal object of this invention to provide novel classes of inhibitors of ICE. These novel classes of ICE inhibitors are characterized by the following structural and physicochemical features:
a) a first and a second hydrogen bonding moiety, each of said moieties being capable of forming a hydrogen bond with a different backbone atom of ICE, said backbone atom being selected from the group consisting of the carbonyl oxygen of Arg-341, the amide —NH— group of Arg-341, the carbonyl oxygen of Ser-339 and the amide —NH— group of Ser-339;
b) a first and a second moderately hydrophobic moiety, said moieties each being capable of associating with a separate binding pocket of ICE when the inhibitor is bound thereto, said binding pocket being selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the P′ binding pocket; and
c) an electronegative moiety comprising one or more electronegative atoms, said atoms being attached to the same atom or to adjacent atoms in the moiety and said moiety being capable of forming one or more hydrogen bonds or salt bridges with residues in the Pi binding pocket of ICE.
It is also an object of this invention to provide a method for identification, design or prediction of ICE inhibitors comprising the steps of:
a) selecting a candidate compound of defined chemical structure comprising at least two hydrogen bonding moieties, at least two moderately hydrophobic moieties and one electronegative moiety comprising one or more electronegative atoms attached either to the same atom or to adjacent atoms in the electronegative moiety;
b) determining a low-energy conformation for binding of said compound to the active site of ICE;
c) evaluating the capability of said compound in said conformation to form at least two hydrogen bonds with the non-carbon backbone atoms of Arg-341 and Ser-339 of ICE;
d) evaluating the capability of said compound in said conformation to associate with at least two of the binding pockets of ICE selected from the group consisting of the P2 binding pocket, the P
Bemis Guy W.
Golec Julian M. C.
Lauffer David J.
Livingston David J.
Mullican Michael D.
Fish & Neave
Haley Jr. James F.
Vertex Pharmaceuticals Incorporated
Wang Min
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