Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-07-20
2001-10-02
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
Reexamination Certificate
active
06297277
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to cysteine protease inhibitors, and more particularly to cysteine protease inhibitors which are peptidyl ketones having heterocyclic leaving groups. The cysteine protease inhibitors of the present invention are particularly designed for the in vivo management of cysteine proteases, particularly cathepsins B, L, H and C, and their primitive enzymatic counterparts.
BACKGROUND TO THE INVENTION
Cysteine proteases associated with human disease states can be grouped into three categories: (1) lysosomal cathepsins; (2) cytosolic calpains; and (3) procaryotic enzymes with autocatalytic activation. Cathepsins B, H, and L are cysteinyl proteases involved in normal protein degradation. As such, they are generally located in the lysosomes of cells. When these enzymes are found extralysosomaly they have been implicated by use of synthetic substrate technology and by natural endogenous inhibitors as playing a causative rote in a number of disease states such as rheumatoid arthritis, osteo arthritis,
Pneumocystis carinii, Schistosomiasis, Trypanosoma cruzi, Trypanosoma brucei brucei, Crithidia fusiculata,
malaria, periodontal disease, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, etc. For example, a connection between cathepsin B-type enzymes and rheumatoid arthritis has been suggested in van Noorden and Everts, “Selective Inhibition of Cysteine Proteinases by Z-Phe-Ala-CH
2
F Suppresses Digestion of Collagen by Fibroblasts and Osteoclasts,” 178
Biochemical and Biophysical Research Communications
178; Rifkin, Vernillo, Kleekner, Auszmann, Rosenberg and Zimmerman, “Cathepsin B and L Activities in Isolated Osteoclasts,” 179
Biochemical and Biophysical Research Communications
63; Grinde, “The Thiol Proteinase Inhibitors, Z-Phe-Phe-CHN
2
and Z-Phe-Ala-CHN
2
, Inhibit Lysosomal Protein Degradation in Isolated Rat Hepatocytes,” 757
Biochimica et Biothysica Acta
15; Mason, Bartholomew and Hardwick, “The Use of Benzyloxycarbonyl[
125
I]iodotyrosylalanyldiazomethane as a Probe for Active Cysteine Proteinases in Human Tissues,” 263
Biochem. J.
945; van Noorden, Smith and Pasnick, “Cysteine Proteinase Activity in Arthritic Rat Knee Joints and tile Effects of a Selective Systemic Inhibitor, Z-Phe-Ala-CH
2
F,” 15
J. Rheumatol.
1525; and van Noorden, Vogels and Smith, “Localization and Cytophotometric Analysis of Cathepsin B Activity in Unfixed and Undecalifed Cryostat Sections of Whole Rat Knee Joints,” 37
J. Histochemistry and Cytochemistry
617. A connection between cathepsin B and osteo arthritis has been suggested in Delaisse, Eeckhout and Vaes, “In Vivo and In Vitro Evidence for the Involvement of Cysteine Proteinases in Bone Resorption,” 125
Biochemical and Biophysical Research Communications
441; a connection between cathepsin B and pneumocystis carinii has been suggested in Hayes, Stubberfield, IcBride and Wilson, “Alterations in Cysteine Proteinase Content of Rat Lung Associated with Development of Pneumocystis Carinii Infection,” 59 Infection and Immunity 3581; a connection between cysteine proteinases and schistosomiasis has been suggested in Cohen, Gregoret, Amiri, Aldape, Railey and McKerrow, “Arresting Tissue Invasion of a Parasite by Protease Inhibitors Chosen With the Aid of Computer Modeling,” 30
Biochemistry
11221. A connection between cysteine proteinases and trypanosoma cruzi, trypanosoma brucei brucei and crithidia fasciculata has been suggested in Ashall, Harris, Roberts, Healy and Shaw, “Substrate Specificity and Inhibitor Sensitivity of a Trypanosomatid Alkaline Peptidase,” 1035
Biochimica et Biophysica Acta
293, and/or in Ashall, Angliker and Shaw, “Lysis of Trypanosomes by Peptidyl Fluoromethyl Ketones,” 170
Biochomical and Biophysical Research Communications
923. A connection between cysteine proteinases and malaria has been suggested in Rosenthal, Wollish, Palmer and Rasnick, “Antimalarial Effects of Peptide Inhibitors or a Plasmodium Falciparum Cysteine Proteinase,” 88
J. Clin. Invest
1467, and in Rosenthal, Lee and Smith, “Inhibition of a Plasmodium Vinckei Cysteine Proteinase Cures lurine Mialaria,” (in press). A connection between cathepsin B and tumor metathesis has been suggested in Smith, Rasnick, Burdick, Cho, Rose and Vahratian, “Visualization of Time-Dependent Inactivation of Human Tumor Cathepsin B Isozymes by a Peptidyl Fluoromethyl Ketone Using a Fluorescent Print Technique,” 8
Anti-cancer Research
525. A connection between cathepsin B and cancer has been suggested in Gordon and Mourad, 2
Blood Coaculation and Fibrinolysis
735. A connection between cathepsin B and periodontal disease has been suggested in Cox, Cho, Eley and Smith, “A Simple, Combined Fluorogenic and Chromogenic Method for the Assay of Proteases in Gingival Crevicular Fluid,” 25
J. Periodont. Res.
164; Uitto, Larjava, Helno and Sorsa, “A Protease of Bacteroides Gingivalis Degrades Cell Surface and M,latrix Glycoproteins of Cultured Gingival Fibroblasts and induces Secretion of Collagenase and Plasminogen Activator,” 57
Infection and Immunitv
213; Kunimatsu, Yamamoto, Ichimaru, Kato and Kato, “Cathepsins B, H and L Activities in Gingival Crevicular Fluid From Chronic Adult Periodontitis Patients and Experimental Gingivitis Subjects,” 25
J Periodont Res
69; Beighton, Radford and Naylor, “Protease Activity in Gingival Crevicular Fluid From Discrete Periodontal Sites in Humans With Periodontitis or Gingivitis”; 35
Archs oral Biol.
329; Cox and Eley., “Preliminary Studies on Cysteine and Serine Proteinase Activities in Inflamed Human Gingiva Using Different 7-Amino-4-Trifluoromethyl Coumarin Substrates and Protease Inhibitors,” 32
Archs oral Biol.
599; and Eisenhauer, Hutchinson, Javed and McDonald, “Identification of a Cathepsin B-Like Protease in the Crevicular Fluid of Gingivitis Patients,” 62
J Dent Res
917. A connection between cathepsin B and metachromatic leukodystrophy has been suggested in von Figura, Steckel, Conary, Hasilik and Shaw, “Heterogeneity in Late-Onset Metachromatic Leukodystrophy. Effect of Inhibitors of Cysteine Proteinases,” 39
Am j Hum Genet.
371; a connection between cathepsin B and muscular leukodystrophy has been suggested in Valentine, Winand, Pradhan, Moise, de Lahunta, Kornegay and Cooper, “Canine X-Linked Muscular Dystrophy as an Animal Model of Duchenne Muscular Dystrophy: A Review,” 42
Am J Hum Genet
352; a connection between cathepsin B and rhinovirus has been suggested in Knott, Orr, Montgomery, Sullivan and Weston, “The Expression and Purification of Human Rhinovirus Protease 3C,” 182
Eur. J. Biochem.
547; a connection between cathepsin B and kidney disease has been suggested in Baricos, O'Connor, Cortez, Wu and Shah, “The Cysteine Proteinase Inhibitor, E-64, Reduces Proteinuria in an Experimental Model of Clomeruloneohritis,” 155
Biochemical and Biophysical Research Communications
1318; and a connection between cathepsin B and multiple sclerosis has been suggested in Dahlman, Rutschmann, Kuehn and Reinauer, “Activation of the Multicatalytic Proreinase from Pat Skeletal Muscle by Fatty Acids or Sodium Dodecyl Sulphate,” 228
Biochem. J.
171.
Connections between certain disease states and cathepsins H and C have also been established. For example, cathepsin H has been directly linked to the causative agents of Pneumocystis carinii and in the neuromuscular diseases Duchenne dystrophy, polymyositis, and neurogenic disorders. Stauber, Riggs and Schochet, “Fluorescent Protease Histochemistry in Neuromuscular Disease,” Neurolooy 194 (Suppl. 1) March 1984; Stauber, Schochet, Riggs, Gutmann and Crosby, “Nemaline Rod Myopathy: Evidence for a Protease Deficiency,”
Neurology
34 (Suppl. 1) March 1984. Similarly, cathepsin C has been directly linked to muscular diseases such as nemaline myopathy, to viral infections, and to processing and activation of bone marrow serine proteases (elastase and granzyme A). McGuire, Lipsky and Thiele, “Generation of Active ivyeloid and Lymphod Granule Serine Proteases Requires Processing by the G
Smith Robert E.
Zimmerman Mary P.
Prototek Inc.
Qazi Sabiha
LandOfFree
Cysteine protease inhibitors containing heterocyclic leaving... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cysteine protease inhibitors containing heterocyclic leaving..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cysteine protease inhibitors containing heterocyclic leaving... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2558122