Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1999-02-22
2000-10-24
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514 19, 514616, 514824, 514825, 514863, 530330, 530331, 558170, 558172, 558173, 562 15, A61K 31662, C07F 940
Patent
active
061367982
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to compounds that inhibit the association of the platelet-derived growth factor receptor and phosphatidylinositol 3-kinase. This invention also relates to pharmaceutical compositions that contain a compound that inhibits the association of the platelet-derived growth factor receptor and phosphatidylinositol 3-kinase, and to methods of treating cancer, restenosis, arthritis, dermatitis, atherosclerosis, vein graft intimal hyperplasia, neointimal hyperplasia of vascular smooth muscle, and psoriasis using compounds that inhibit the association of the platelet-derived growth factor receptor and phosphatidylinositol 3-kinase.
BACKGROUND OF THE INVENTION
Many disease states are characterized by the uncontrolled proliferation and differentiation of cells. These disease states encompass a variety of cell types and maladies such as cancer, atherosclerosis, restenosis, arthritis, dermatitis, vein graft intimal hyperplasia, neointimal hyperplasia of vascular smooth muscle and psoriasis. The compounds can also be used to delay aging of the skin. The proliferation, differentiation and survival of cells are regulated by numerous extracellular signaling polypeptide growth factors, which have been implicated in these disease states. Some of the better characterized growth factors include the following: epidermal growth factor (EGF), fibroblast growth factors (FGFs), and platelet-derived growth factor (PDGF).
The effects of many growth factors are known to be mediated by high affinity receptor tyrosine kinases. The binding of growth factors to extracellular receptors activates intracellular tyrosine kinases that catalyze the phosphorylation of several tyrosines on intracellular protein substrates or the receptor (autophosphorylation). These phosphorylated tyrosines create high affinity binding sites for many secondary cellular proteins involved in signal transduction such as phosphatidylinositol 3-kinase (PI 3-kinase), phospholipase C-.gamma. (PLC-.gamma.), and ras-GTPase-activating protein (GAP), among others. These molecules contain homologous regions known as src homology 2 (SH2) domains that were first identified in src family protein tyrosine kinases (PTKs). SH2 domains confer high affinity interactions with specific phosphorylated tyrosine residues of the growth factor receptors. Further downstream signaling results in cellular proliferation. Thus, the blockade of these signal transduction pathways can be used in the treatment of proliferative diseases.
In particular, the binding of PDGF to cell surface receptors induces receptor dimerization, followed by autophosphorylation at multiple tyrosine residues, which initiates cytoplasmic signaling via secondary cellular proteins containing SH2 domains. Currently, more than twenty cytosolic proteins likely to be involved in signaling have been shown to contain SH2 domains. Of these, PI 3-kinase is an important member that interacts with many activated PTKs and is involved in both normal and oncogenic signal transduction. The role of PI 3-kinase in PDGF-mediated cell proliferation has been investigated by measuring the levels of DNA synthesis in NMuMG cells expressing wild-type versus those expressing mutant PDGF receptors. A significant increase in DNA synthesis was observed in cells expressing PDGF receptors that were specifically associated with PI 3-kinase. The important involvement of PI 3-kinase in cell motility was recently demonstrated by Wennstrom et al., Oncogene, 1994;9:651-60, who showed that in porcine aortic endothelial cells expressing the PDGF-.beta. receptor, membrane ruffling and chemotaxis transduced by the PDGF-.beta. receptor required PI 3-kinase binding.
PI 3-kinase is a heterodimeric enzyme and contains an 85 kDa (p85) noncatalytic subunit and a 110 kDa (p110) catalytic subunit. The p85 subunit has one src homology 3 (SH3) and two SH2 domains which bind to specific phosphorylated tyrosines on activated growth factor receptors. PI 3-kinase has been shown to interact specifically with the phosphorylated
REFERENCES:
patent: 5382569 (1995-01-01), Cody et al.
patent: 5763577 (1998-06-01), Bolton et al.
PCT International Search Report, mailing date: Oct. 7, 1997.
Ramalingam, K., et al., "Structure-Activity Studies of Phosphorylated Peptide Inhibitors of the Association of Phosphatidylinositol 3-Kinase with PDGF-.beta. Receptor," Bioorganic & Medicinal Chemistry, 1995, vol. 3, No. 9, pp. 1263-1272.
Eaton, S. R., et al., "Structure-Activity Relationships of Peptides That Block the Association of PDGF-.beta. Receptor with Phosphatidylinositol 3-Kinase," Peptides: Chemistry, Structure and Biology, Proceedings of the 14.sup.th American Peptide Symposium, eds. Kaumaya, P. T. P., and Hodges, R. S., 1996, Kinswinford: Mayflower Scientfic Ltd., pp. 414-415.
Ramalingam, K., et al., "Side reactions in the synthesis of phosphotyrosine-containing peptides," Letters in Peptide Science, 1994, vol. 1, pp. 73-79.
Domchek, S. M., et al., "Inhibition of SH2 Domain/Phosphoprotein Association by a Nonhydrolyzable Phosphonopeptide," Biochemistry, 1992, vol. 31, pp. 9865-9870.
Burke, Jr., T. R., et al., "Potent Inhibition of Insulin Receptor Dephosphorylation by a Hexamer Peptide Containing the Phosphotyrosyl Mimetic F.sub.2 Pmp," Biochemical and Biophysical Research Communications, Oct. 14, 1994, vol. 204, No. 1, pp. 129-134.
Burke, Jr., T. R., et al., "Nonhydrolyzable Phosphotyrosyl Mimetics for the Preparation of Phosphatase-Resistant SH2 Domain Inhibitors," Biochemistry, 1994, vol. 33, pp. 6490-6494.
Klippel, A., et al., "The C-Terminal SH2 Domain of p85 Accounts for the High Affinity and Specificity of the Binding of Phosphatidylinositol 3-Kinase to Phosphorylated Platelet-Derived Growth Factor .beta. Receptor," Molecular and Cellular Biology, Apr., 1992, vol. 12, No. 4, pp. 1451-1459.
Burke, Jr., T. R., et al., "Cyclic Peptide Inhibitors of Phosphatidylinositol 3-Kinase p85 SH2 Domain Binding," Biochemical and Biophysical Research Communications, Jun. 30, 1994, vol. 201, No. 3, pp. 1148-1153.
Roller, P. P., et al., "Norleucine as a Replacement for Methionine in Phosphatase-Resistant Linear and Cyclic Peptides which Bind to P85 SH2 Domains," Bioorg. Med. Chem Lett., 1994, vol. 4, No. 15, pp. 1879-1882.
Fantl, W. J., et al., "Distinct Phosphotyrosines on a Growth Factor Receptor Bind to Specific Molecules That Mediate Different Signaling Pathways," Cell, 1992, vol. 69, pp. 413-423.
Eaton, S. R., et al., "Proline Modifications of a Phosphotyrosine Pentapeptide from the PDGF .beta.-Receptor," 24.sup.th National Medicinal Chemistry Symposium, Jun., 1994, poster presentation.
Ramalingam, K., et al., "Structure-Activity Studies of Peptide Inhibitors for the Binding of SH2 Domains of the p85 Subunit of Phosphatidylinositol 3-Kinase with the PDGF-.beta. Receptor," 208.sup.th American Chemical Society National Meeting, Aug., 1994, poster presentation.
Eaton, S. R., et al., "Structure-Activity Relationships of Peptides that Block the Association of PDGF .beta.-Receptor with Phosphatidylinositol 3-Kinase," 14.sup.th American Peptide Symposium, Jun., 1995, poster presentation.
Ramalingam, K., et al, "Use of Boc-Tyr[PO.sub.3 (Bzl).sub.2 ]-OH in the Synthesis of Methionine Containing Phosphopeptides," ACS Regional Meeting, Ann Arbor, Jun., 1994, poster presentation.
Cody Wayne Livingston
Doherty Annette Marian
Eaton Scott R.
Panek Robert Lee
Ashbrook Charles W.
Kumar Shailendra
Warner-Lambert & Company
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