Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 4 to 5 amino acid residues in defined sequence
Reexamination Certificate
1991-12-17
2002-02-19
Eyler, Yvonne (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
4 to 5 amino acid residues in defined sequence
C530S331000, C514S018700, C514S019300
Reexamination Certificate
active
06348570
ABSTRACT:
BACKGROUND OF THE INVENTION
The instant invention concerns novel chromophore containing compounds useful in determining Interleukin-1&bgr; convertase activity. Interleukin-1&bgr; convertase (ICE) has been identified as the enzyme responsible for converting precursor interleukin-1&bgr; (IL-1&bgr;) to biologically active IL-1&bgr;. Compounds of Formulas I and II are useful in the diagnosing and monitoring IL-1 mediated dieases or in evaluation inhibitors of interleukin-1&bgr; convertase.
Mammalian interleukin-1 (IL-1) is an immunoregulatory protein secreted by cell types as part of the inflammatory response. The primary cell type responsible for IL-1 production is the peripheral blood monocyte. Other cell types have also been described as releasing or containing IL-1 or IL-1 like molecules. These include epithelial cells (Luger, et al., J. Immunol. 127: 1493-1498 (1981), Le et al., J. Immunol. 138: 2520-2526 (1987) and Lovett and Larsen, J. Clin. Invest. 82: 115-122 (1988), connective tissue cells (Ollivierre et al., Biochem. Biophys. Res. Comm. 141: 904-911 (1986), Le et al, J. Immunol. 138: 2520-2526 (1987), cells of neuronal origin (Giulian et al., J. Esp. Med. 164: 594-604 (1986) and leukocytes (Pistoia et al., J. Immunol. 136: 1688-1692 (1986), Acres et al., Mol. Immuno. 24: 479-485 (1987), Acres et al., J. Immunol. 138: 2132-2136 (1987) and Lindenmann et al., J. Immunol 140: 837-839 (1988).
Biologically active IL-1 exists in two distinct forms, IL-1&agr; with an isoelectric point of about pI 5.2 and IL-1&bgr; with an isoelectric point of about 7.0 with both forms having a molecular mass of about 17,500 (Bayne et al., J. Esp. Med. 163: 1267-1280 (1986) and Schmidt, J. Esp. Med. 160: 772 (1984). The polypeptides appear evolutionarily conserved, showing about 27-33% homology at the amino acid level (Clark et al., Nucleic Acids Res. 14: 7897-7914 (1986).
Mammalian IL-1 is synthesized as a cell associated precursor polypeptide with a molecular mass of about 31.4 kDa (Limjuco et al., Proc. Natl. Acad. Sci USA 83: 3972-3976 (1986). Precursor IL-1&bgr; is unable to bind to IL-1 receptors and is biologically inactive (Mosley et al., J. Biol. Chem. 262: 2941-2944 (1987). Biological activity appears dependent upon some form of proteolytic processing which results in the conversion of the precursor 31.5 kDa form to the mature 17.5 kDa form. Evidence is growing that by inhibiting the conversion of precursor IL-1&bgr; to mature IL-1&bgr;, one can effectively inhibit the activity of interleukin-1.
Mammalian cells capable of producing IL-1&bgr; include, but are not limited to, karatinocytes, endothelial cells, mesangial cells, thymic epithelial cells, dermal fibroblasts, chondrocytes, astrocytes, glioma cells, mononuclear phagocytes, granulocytes, T and B lymphocytes and NK cells.
As discussed by J. J. Oppenheim, et al. Immunology Today, vol. 7(2):45-56 (1986), the activities of interleukin-l are many. It has been observed that catabolin, a factor that promotes degradation of cartilage matrix, also exhibited the thymocyte comitogenic activities Qf IL-1 and stimulates chondrocytes to release collagenase neutral proteases and plasminogen activator. In addition, a plasma factor termed proteolysis inducing factor stimulates muscle cells to produce prostaglandins which in turn leads to proteolysis, the release of amino acids and, in the long run, muscle wasting, and appears to represent a fragment of IL-1 with fever-inducing, acute phase response and thymocyte co-mitogenic activities.
IL-1 has multiple effects on cells involved in inflammation and wound healing. Subcutaneous injection of IL-1 leads to margination of neutrophils and maximal extravascular infiltration of the polymorphonuclear leukocytes (PMN). In vitro studies reveal IL-1 to be a chemotactic attractant for PMN to activate PMN to metabolize glucose more rapidly to reduce nitroblue tetrazolium and to release their lysozomal enzymes. Endothelial cells are stimulated to proliferate by IL-1 to produce thromboxane, to become more adhesive and to release procoagulant activity. IL-1 also enhances collagen type IV production by epidermal cells, induces osteoblast proliferation and alkaline phosphatase production and stimulates osteoclasts to resorb bone. Even macrophages have been reported to be chemotactically attracted to IL-1 to produce prostaglandins in response to IL-1 and to exhibit a more prolonged and active tumoricidal state.
IL-1&bgr; is also a potent bone resorptive agent capable upon infusion into mice of causing hypercaleemia and increas in bone resorptive surface as revealed by his to morphometry Sabatini, M. et al., PNAS 85: 5235-5239, 1988.
Accordingly, IL-1 has been implicated in infectious diseases where active infection exists at any body site, such as meningitis and salpingitis; complications of infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody, and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis. Immune-based diseases which may be responsive to ICE inhibitors of Formula I include but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host-disease; auto-immune diseases including Type I diabetes mellitus and multiple sclerosis. IL-1 has also been implicated in the treatment of bone and cartilage resorption as well as diseases resulting in excessive deposition of extracellular matrix. Such diseases include periodonate diseases interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, and keloid formation.
SUMMARY OF THE INVENTION
Disclosed are novel chromophore containing compounds of Formula I and their use in determining interleukin-1&bgr; convertase (ICE) activity. Compounds of Formula II are useful in the diagnosing and monitoring IL-1 mediated dieases or in evaluation inhibitors of interleukin-1&bgr; convertase.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment the invention concerns a chromophore compound of Formula I
wherein:
AA
1
, is independently selected from the group consisting of
(a) a single bond, and
(b) an amino acid of formula AI
wherein R
1
selected from the group consisting of
(a) hydrogen,
(b) substituted C
1-6
alkyl, wherein the substituent is selected from
(1) hydrogen,
(2) hydroxy,
(3) halo,
(4) —S—C
1-4
alkyl,
(5) —SH
(6) C
1-6
alkylcarbonyl,
(7) carboxy,
(9) C
1-4
alkylamino, wherein the alkyl moeity is substituted with hydrogen or hydroxy, and the amino is substituted with hydrogen or CBZ,
(10) guanidino,
(11) amino, and
(c) aryl C
1-6
alkyl or substituted aryl C
1-6
alkyl wherein,
the aryl group is selected from the group consisting of:
(a) phenyl,
(b) naphthyl,
(c) pyridyl,
(d) furyl,
(e) thienyl,
(f) thiazolyl,
(g) isothiazolyl,
(h) imidazolyl,
(i) benzimidazolyl,
(j) pyrazinyl,
(k) pyrimidyl,
(l) quinolyl,
(m) isoquinolyl,
(n) benzofuryl,
(o) benzothienyl,
(p) pyrazolyl,
(q) indolyl,
(r) purinyl,
(s) isoxazolyl, and
(t) oxazolyl, and mono and di-substituted aryl as defined above in items (a) to (t) wherein the substitutents are independently C
1-6
alkyl, halo, hydroxy, C
1-6
alkyl amino, C
1-6
alkoxy, C
1-6
alkylthio, and C
1-6
alkylcarbonyl;
AA
2
is independently selected from the group consisting of
(a) a single bond, and
(b) an amino acid of formula AII
AA
3
, which are each independently selected from the group consisting of
(a) a single bond, and
(b) an amino acid of formula AIII
wherein R
2
and R
3
are each independently selected from the group consisting of
(a) hydrogen,
(b) substituted C
1-6
alkyl, wherein the substituent is selected from
(1) hydrogen,
(2) hydroxy,
(3) halo,
(4) —S—C
1-4
alkyl,
(5) —SH
(6) C
1-6
alkylcarbonyl,
(7) carboxy,
(9) C
1-4
alkylamino, wherein the alkyl moeity is substituted with hydrogen or hydroxy, and the amino is substi
Chapman Kevin T.
Hagmann William K.
Maccoss Malcolm
Mumford Richard A.
Thornberry Nancy A.
Eyler Yvonne
Merck & Co. , Inc.
Panzer Curtis C.
Rose David L.
Yuro Raynard
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