Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-18
2004-05-04
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S185000, C534S010000, C540S121000, C540S145000, C540S465000, C540S471000, C540S474000
Reexamination Certificate
active
06730666
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to inhibition of growth factor tyrosine kinase receptor activity, particularly inhibition of angiogenesis and related disorders, tumor progression and growth factor related skeletal disorders, by porphyrin and corrole compounds, and to certain novel porphyrin compounds.
ABBREVIATIONS: AP, alkaline phosphalase; EGF, epidermal growth factor; bFGF, basic fibroblast growth factor; FGF, fibroblast growth factor, FGFR, FGF receptor, FGFR-1, FGF receptor-1; FGFR-3, FGF receptor-3; UP, FGFR-1-alkaline phosphatase fusion protein; FR3-AP, FGFR-3-alkaline phosphatase fusion protein; HB-EGF, heparin-binding EGF-like growth factor; HGF, hepatocyte growth factor, HSPG, heparan sulfate proteoglycans; IGF, insulin-like growth factor, LLC, Lewis Lung Carcinoma; NGF, nerve growth factor, PDGF, plateleterived growth factor; SMC, smooth muscle cells; TKR, tyrosine kinase receptor; VEGF, vascular endothelial growth factor, VSMC, vascular smooth muscle cells.
BACKGROUND OF THE INVENTION
Growth factors play a pivotal role in the multistep pathway of cell differentiation and migration, tumor and metastasis progression, and angiogenesis.
The pathological mechanism of many proliferative diseases is determined by biological events such as growth factor receptor stimulation, autophosphorylation, and the phosphorylation of intracellular protein substrates.
Phosphorylation of tyrosine residues on protein substrates in normal cells serves a critical function in intracellular growth signaling pathways initiated by stimulated extracellular growth factor receptors. Growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), vascular endotheial growth factor (VEGF) and hepatocyte growth factor (HGF), associate with their respective extracellular receptors thus activating the intracellular tyrosine kinase domains of said receptors and catalyzing the phosphorylation of the receptors themselves (autophosphorylation) or of intracellular substrates. This association between the growth factor ligand and the respective receptor simulates tyrosine kinase activity as one of the initial biochemical events leading to DNA synthesis and cell division Therefore, compounds which inhibit protein tyrosine kinases associated with intracellular growth factor signal transduction pathways may be useful for the treatment of cellular proliferative disorders.
Fibroblast growth factors (FGFs) are abundant m normal and malignantly transformed cells and play a pivotal role in the multistep pathway of malignant transformation, tumor progression, metastasis and angiogenesis. In adults, bFGF, as well as the FGF oncogenes HST (FGF4) and int-2 (FGF-3) are found in tumors such as stomach cancer, Kaposi's sarcoma, melanoma and breast cancer.
FGFs bind avidly to the glycosaminoglycan heparin and to heparan sulfate proteoglycans (HSPG) found on cells and in the extracellular matrix. Studies on the mode of action of FGFs identified a novel role for beparin-like molecules in the formation of distinct FGF-heparin complexes that are essential for binding of FGF to its cognate receptor (Yayon et al, 1991; Rapraeger et al, 1991). We and others have recently addressed the importance of specific heparin and heparan sulfate structures in FGF receptor binding activity (Guimond et al, 1993; Aviezer et al, 1994a) and have demonstrated that specific HSPGs such as perlecan, function as a low affinity, accessory receptor for bFGF and as a potent angiogenic modulator (Aviezer et al, 1994b).
FGF receptors were found to play a role in genetically acquired growth disorders. Thus, a number of mutations in FGF receptors have been implicated in various forms of human skeletal dysplasias. For instance, achondroplasia, the most common form of human dwarfism, is caused by a pecfic mutation in the transmembrane domain of FGFR-3 (Rousseau et al, 1994; Shiang et al, 1994). Other skeletal disorders such as Crouzon's syndrome and thanatophoric dysplasia, involve mutations in the extracellular domain (Reardon et al, 1994) or the kinase domain of FGF receptors. In achondroplasia, a point mutation (Gly-380/Arg) in the transmembrane domain of FGFR-3 leads to impaired growth. Since we have identified FGF-9 as a putative ligand for FGFR-3 (Hecht et al, 1995), it is conceivable that strategies aimed at check points along the biochemical mechanism of the FGFR-3 activation pathway, may result in treatment of achondroplasia Naski et al, 1996, have demonstrated that both the achondroplasia and thanatophoric dysplasia mutations constitutively activate the receptor as evidenced by receptor tyrosine phosphorylation. These findings have been biologically supported by knock out of the FGFR-3 gene (Deng et al, 1996). Furthermore, it seems that FGFRs are involved in bone and cartilage benign tumors, such as hereditary multiple exostosis, osteoarthritis and others. Exostosis is an osteocartilaginous benign tumor of an autosomal dominance, diversed phenotype and heterogeneous genetics characterized by the formation of cartilaginous capped metaphyseal bony protrusions.
Vascular endothelial growth factor (VEGF) is a known endothelial mitogen and a potent enhancer of vascular permeability. VEGF is a multifunctional cytoline that exerts in vivo a key role in physiological and pathological neoangiogenesis by stimulating endothelial cell proliferation and vessel hyperpermeability, VEGF exists as one of four different isoforms, respectively, VEGF 121, VEGF 165, VBGF 199, and VEGF 206. VEGF121 does not bind heparin while the other three isoforms do, and it has been documented that the binding of VEGF165 to its receptor is dependent upon cell surface heparin suite proteoglycans (Gitay-Goren et al, 1992). VEGF binds to Fit-1 and Flk-1/KDR cell membrane receptors which are members of the tyrosine kinase receptor family. VEGF seems to be a crucial mediator of physiological neoangiogenesis during the embryonic development and the female cycle.
VEGF also has a major role in the pathogenesis of many diseases including hypervascularized tumors, rheumatoid arthritis, cutaneous diseases and proliferative retinopathies. VEGF gene expression in vitro is enhanced approximately ten times by hypoxia. Current evidence (Patt et al, 1998) suggests that hypoxia is also the driving force for VEGF gene expression in cells in vivo and represents the most important trigger for tumor angiogenesis and edema. Recent approaches to inhibit tumor angiogenesis and metastasis formation concentrate on the disruption of VEGF/VEGF receptor signal transduction pathway in vivo. Persistent angiogenesis may cause or exacerbate certain diseases such as psoriasis, rheumatoid arthritis, hemangiomas, angiofibromas, diabetic retinopathy and neovascular glaucoma. An inhibitor of VEGF activity would be useful as a treatment for such diseases and other VEGF-induced pathological angiogenesis and vascular permeability conditions, such as tumor vascularization.
The EGF receptor, which main ligands are EGF, HB-EGF and transforming growth factor &agr; (TGF-&agr;), is involved in the disease processes of many malignant tumors, especially colon and breast cancers. Overexpression and mutation of the closely related Erb-2 and Erb-3 receptors have been shown to be the major risk factors in poor prognosis of breast cancer. HB-EGF is a most potent activator of the EGF receptor on smooth muscle cells (SMC), including VSMC, playing a crucial role in the pathogenesis of atherosclerosis and benign hypertrophy of the uterus and the formation of leiomyomas (tumors composed of nonstriated muscular tissue).
PDGF has been identified as a potent endogenous vascular smooth muscle cells (VSMC) mitogen and chemoattractant. Proliferation and directed migration of VSMC are important elements in processes such as vascular remodeling, atherosclerosis and restenosis. In balloon-injured rat model, elevated vascular mRNA expression of PDGF A and B chains and PDGF receptors has been observed in carotid arteries (J. Cell Biology
Aviezer David
Gross Zeev
Yayon Avner
Browdy and Neimark
Ford John M.
Yeda Research and Development Co. Ltd.
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