Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-07
2001-10-30
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S417000, C514S255030, C540S524000, C548S477000, C544S405000
Reexamination Certificate
active
06310057
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to &agr;-ketoamide inhibitors of multicatalytic protease (MCP), to compositions including such inhibitors, and to methods for the use of MCP inhibitors. The MCP inhibitors of the present invention are useful, for example, to retard loss of muscle mass incident to various physiological states.
BACKGROUND OF THE INVENTION
Eukaryotic cells constantly degrade and replace cellular protein. This permits the cell to selectively and rapidly remove proteins and peptides having abnormal conformations, to exert control over metabolic pathways by adjusting levels of regulatory peptides, and to provide amino acids for energy when necessary, as in starvation. See Goldberg, A. L. & St. John, A. C.
Annu. Rev. Biochem.
45:747-803 (1976). The cellular mechanisms of mammals allow for multiple pathways for protein breakdown. Some of these pathways appear to require energy input in the form of adenosine triphosphate (“ATP” ). See Goldberg, A. L. & St. John, supra.
Multicatalytic protease (MCP, also referred to as “multicatalytic proteinase,” “proteasome,” “multicatalytic proteinase complex,” “multicatalytic endopeptidase complex,” “20S proteasome” and “ingensin”) is a large molecular weight (700 kD) eukaryotic cytoplasmic proteinase complex which plays a role in at least two cellular pathways for the breakdown of protein to peptides and amino acids. See Orlowski, M.
Biochemistry
29(45) 10289-10297 (1990). The complex has at least three different types of hydrolytic activities: (1) a trypsin-like activity wherein peptide bonds are cleaved at the carboxyl side of basic amino acids; (2) a chymotrypsin-like activity wherein peptide bonds are cleaved at the carboxyl side of hydrophobic amino acids; and (3) an activity wherein peptide bonds are cleaved at the carboxyl side of glutamic acid. See Rivett, A. J.
J. Biol. Chem.
264:21 12215-12219 (1989) and Orlowski, supra.
One route of protein hydrolysis which involves MCP also involves the polypeptide “ubiquitin.” Hershko, A. & Ciechanover A.
Annu. Rev. Biochem.
51:335-364 (1982). This route, which requires MCP, ATP and ubiquitin, appears responsible for the degradation of highly abnormal proteins, certain short-lived normal proteins and the bulk of proteins in growing fibroblasts and maturing reticuloytes. See Driscoll, J. and Goldberg, A. L.
PNAS
86:787-791 (1989). Proteins to be degraded by this pathway are covalently bound to ubiquitin via their lysine amino groups in an ATP-dependent manner. The ubiquitin-conjugated proteins are then degraded to small peptides by an ATP-dependent protease complex by the 26S proteasome, which contains MCP as its proteolytic core. Goldberg, A. L. & Rock, K. L.
Nature
357:375-379 (1992).
A second route of protein degradation which requires MCP and ATP, but which does not require ubiquitin, has also been described. See Driscoll, J. & Goldberg, A. L., supra. In this process, MCP hydrolyzes proteins in an ATP-dependent manner. See Goldberg, A. L. & Rock, K. L., supra. This process has been observed in skeletal muscle. See Driscoll & Goldberg, supra. However, it has been suggested that in muscle, MCP functions synergistically with another protease, multipain, thus resulting in an accelerated breakdown of muscle protein. See Goldberg & Rock, supra.
The relative activities of cellular protein synthetic and degradative pathways determine whether protein is accumulated or lost. The abnormal loss of protein mass is associated with several disease states such as muscular dystrophy, cardiac cachexia, emphysema, leprosy, malnutrition, osteomalacia, child acute leukemia, and cancer cachexia. Loss of muscle mass is also observed in aging, long term hospitalization or long term confinement to bed, and in chronic lower back pain.
With denervation or disuse, skeletal muscles undergo rapid atrophy which leads to a profound decrease in size, protein content and contractile strength. This atrophy is an important component of many neuromuscular diseases in humans. Enhancement of protein breakdown has been implicated as the primary cause of muscle wasting in denervation atrophy, See Furono, K. et al.
J. Biochem.
265/15:8550-8557 (1990). While the specific process or processes involved in protein hydrolysis in muscle has not been identified, evidence is available linking the involvement of MCP in the accelerated breakdown of muscle proteins. See, for example, Furono, supra, and PCT Published Application WO 92/20804 (publication date: Nov. 26, 1992).
The levels of several proteins responsible for cell cycle regulation are controlled through ubiquitin-dependent degradation by the proteasome. Among these proteasome substrates are the tumor supressor protein p53 (Schneffer, M. et al.
Cell
75:495-505 (1993)), the cyclin-dependent kinase inhibitor p27 (Pagano, M. et al.,
Science
269:682-685 (1995), and cyclin B (Glotzer, M. et al.,
Nature
349:132-138 (1991). Inappropriate degradation of these key regulatory proteins by ubiquitin-dependent proteolysis has been correlated with the development of tumors in the case of p53 and human papillomavirus-containing cervical carcinomas (Schneffer, M. et al.,
PNAS
88: 5523-5527 (1991); Hubbert, N. et al.,
J. Virol.
66:6237-6241 (1992)) and in the example of p27 in colorectal carcinomas (Loda, M. et al.,
Nature Med.
3:231-234 (1997)). Additionally, high levels of p27 are associated with a positive clinical outcome in colon carcinoma (Loda, supra; Fredersdorf. S. et al.,
PNAS
94:6380-6385)), breast carcinomas (Catzavalos, C. et al.
Nature Med.
3:227-230 (1997); Porter, P. et al.,
Nature Med.
3:222-225 (1997); Fredersdorf, supra) and gastric carcinoma (Mori, M. et al.
Nature Med.
3:593 (1997)). Treatment of transformed cells with proteasome inhibitors has been reported to result in accumulation of p27 (Drexler, H. C. A.
PNAS
94:855-860 (1997)) and p53 (Shinohara, K. et al.
Biochem J.
317:385-388 (1996); Lopes, U. et al.
J. Biol. Chem.
272:12893-12896 (1997)) and to trigger apoptotic death of the cells. Therefore, compounds which inhibit the degradation of these growth inhibitory factors would be expected to cause cell cycle arrest and would be useful in the treatment of cancer and other proliferative diseases, including psoriasis and restenosis.
The transcription factor NF-&kgr;B stimulates expression of a wide variety of genes important in immune and inflammatory responses (Bauerle, P. and Henkel, T.
Annu. Rev. Immunol.
12:141-179 (1994)). In unstimulated cells, NF-&kgr;B exists as an inactive cytoplasmic complex with an inhibitor protein, I&kgr;B. Upon stimulation of the cells, the I&kgr;B protein is ubiquitinated and degraded by the proteasome, activating NF-&kgr;B (Palombella, V. et al.
Cell
78:773-785 (1994)). The resulting free NF-&kgr;B enters the cell nucleus where it initiates transcription.
Activation of NF-&kgr;B results in production of inflammatory cytokines such as tumor necrosis factor a, interleukin-2 and interleukin-6, and cell adhesion molecules including intracellular cell adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1-(VCAM-2), and E-selectin (Baeuerle and Henkel, supra). Suppression of the activation of NF-&kgr;B through inhibition of the proteasome would therefore provide a method for treatment of inflammatory conditions including arthritis, sepsis, and inflammatory bowel disease.
Activation of the cellular apoptotic program is a current strategy for treatment of human cancers. It has been demonstrated that X-irradiation and standard chemotherapeutic drugs kill some tumor cells through induction of apoptosis (Fisher, D. E.
Cell
78, 539-542 (1994)). Unfortunately, the majority of human cancers at present are resistant to these therapies (Harrison, D. J. J.
Patho.
175, 7-12(1995)). Activation of NF-&kgr;B has been demonstrated to render some tumor cells resistant to the pro-apoptotic effects of TNF-&agr;, cancer chemotherapeutic agents and radiation (Beg, A. And Baltimore, D.
Science
274, 782-784(1996); Wang, C. Y. et al.,
Science
274, 784-787 (1996); Van Antwerp D., et al.,
Scien
Chatterjee Sankar
Mallamo John P.
Cephalon Inc.
Powers Fiona T.
Woodcock Washburn Kurtz Mackiewicz & Norris LLP
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