The integrin αvβ3 (also known as vitronectin receptor), is a member of the integrin family of heterodimeric transmembrane glycoprotein complexes that mediate cellular adhesion events and signal transduction processes. Integrin αvβ3 is expressed in number of cell types and has been shown to mediate several biologically relevant processes, including adhesion of osteoclasts to the bone matrix, vascular smooth muscle cell migration and angiogenesis.
The integrin avb3 has been shown to play a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, osteopenia, angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis artherosclerosis). The compounds of the present invention are αvβ3 antagonists and can be used, alone or in combination with other therapeutic agents, in the treatment or modulation of various conditions or disease states described above. Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials
The integrin αvβ5 plays a role in neovascularization. For instance, M. C. Friedlander, et al., Science, 270, 1500-1502 (1995) disclose that a monoclonal antibody for αvβ5 inhibits VEFG-induced angiogenesis in the rabbit cornea and the chick chorioallantoic membrane model. Therefore the compounds of this invention which act as antagonists of the αvβ5 integrin will inhibit neovascularization and will be useful for treating and preventing angiogenesis metastasis, tumor growth, macular degeneration and diabetic retionopathy.
It has been shown that the αvβ3 integrin and other αv containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to αvβ3 also bind to αvβ3, αvβ1 and αIIbβ3. Antagonism of platelet αIIbβ3 (also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin αvβ3, it would be beneficial to develop compounds which are selective antagonists of αvβ3 as opposed to αIIbβ3. Additionally, it may be beneficial to develop compounds that are selective against the β1, β6, and β8 integrin subunits to further reduce toxicity.
Certain compounds of this invention antagonize both the αvβ5 and the αvβ3 receptor and therefore are referred to as “mixed αvβ5/αvβ3 antagonists” or “dual αvβ3/αvβ5 antagonists”. Such dual or mixed antagonists are useful for treating or preventing angiogenesis, tumor metastasis, tumor growth, diabetic retinopathy, macular degeneration, atherosclerosis and osteoporosis. The compounds of the present invention further show greater selectivity for the αvβ3 and/or αvβ5 integrin than for the αvβ5 integrin. It has been found that the selective antagonism of the αvβ3 integrin is desirable in that the αvβ6 integrin may play a role in normal physiological processes of tissue repair and cellular turnover that routinely occur in the skin and pulmonary tissue. Therefore, compounds of the present invention which selectively inihibit the αvβ3 integrin as opposed to the αvβ6 integrin have reduced side-effects associated with inhibtion of the αvβ6 integrin.
The compounds of this invention are therefore 1) αvβ3 integrin antagonists; or 2) αvβ5 integrin antagonists; or 3) mixed or dual αvβ3/αvβ5 antagonists. The present invention includes compounds which inhibit the respective integrins and also includes pharmaceutical compositions comprising such compounds. The present invention further provides for methods for treating or preventing conditions mediated by the αvβ3 and/or αvβ5 receptors in a mammal in need of such treatment comprising administering a therapeutically effective amount of the compounds of the present invention and pharmaceutical compositions of the present invention. Administration of such compounds and compositions of the present invention inhibits angiogenesis, tumor metastasis, tumor growth, osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, retinopathy, macular degeneration, arthritis, periodontal disease, smooth muscle cell migration, including restenosis and artherosclerosis, and viral diseases.
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the αvβ3 integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin αvβ3 expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the αvβ3 integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of αvβ3 provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of αvβ3 antagonists causes dramatic regression of various histologically distinct human tumors.
The compounds of the present invention are useful for the treatment, including prevention of angiogenic disorders. The term angiogenic disorders include conditions involving abnormal neovascularization. The growth of new blood vessels, or angiogenesis, also contributes to pathological conditions such as diabetic retinopathy including macular degeneration (Adamis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992), 1135-1138). Therefore, αvβ3 antagonists would be useful therapeutic agents for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
It has been reported that the cell surface receptor αvβ3 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of αvβ3 have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of αvβ3 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast αvβ3 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.
The role of the αvβ3 integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994) 125-34). Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial.
White (Current Biology, Vol. 3(9)(1993) 596-599) has reported that adenovirus uses αvβ3 for entering host cells. The integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit αvβ3 would find usefulness as antiviral agents.
M. C. Friedlander, et al., Science, 270, 1500-1502 (1995) disclose that a monoclonal antibody for αvβ5 inhibits VEFG-induced angiogenesis in the rabbit cornea and the chick chorioallantoic membrane model.