Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Reexamination Certificate
2001-06-29
2003-07-08
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
C514S277000, C514S461000, C514S438000
Reexamination Certificate
active
06589997
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to various therapeutic uses of small molecule compounds having either hepatocyte growth factor/scatter factor (HGF/SF) activity, or the property of inhibiting the activity of HGF/SF. Such compounds have the potential for the treatment of conditions and diseases in which modulation of cellular proliferation, among other activities, is desired.
BACKGROUND OF THE INVENTION
Scatter factor (SF; also known as hepatocyte growth factor [HGF], and hereinafter referred to and abbreviated as HGF/SF) is a pleiotropic growth factor that stimulates cell growth, cell motility, morphogenesis and angiogenesis. HGF/SF is produced as an inactive monomer (~100 kDa) which is proteolytically converted to its active form. Active HGF/SF is a heparin-binding heterodimeric protein composed of a 62 kDa &agr; chain and a 34 kDa &bgr; chain. HGF/SF is a potent mitogen for parenchymal liver, epithelial and endothelial cells (Matsumoto, K, and Nakamura, T., 1997, Hepatocyte growth factor (HGF) as a tissue organizer for organogenesis and regeneration. Biochem. Biophys. Res. Commun. 239, 639-44; Boros, P. and Miller, C. M., 1995, Hepatocyte growth factor: a multifunctional cytokine. Lancet 345, 293-5). It stimulates the growth of endothelial cells and also acts as a survival factor against endothelial cell death (Morishita, R, Nakamura, S, Nakamura, Y, Aoki, M, Moriguchi, A, Kida, I, Yo, Y, Matsumoto, K, Nakamura, T, Higaki, J, Ogihara, T, 1997, Potential role of an endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes. Diabetes 46:138-42). HGF/SF synthesized and secreted by vascular smooth muscle cells stimulate endothelial cells to proliferate, migrate and differentiate into capillary-like tubes in vitro (Grant, D. S, Kleinman, H. K., Goldberg, I. D., Bhargava, M. M., Nickoloff, B. J., Kinsella, J. L., Polverini, P., Rosen, E. M., 1993, Scatter factor induces blood vessel formation in vivo. Proc. Natl. Acad. Sci. U S A 90:1937-41; Morishita, R., Nakamura, S., Hayashi, S., Taniyama, Y., Moriguchi, A., Nagano, T., Taiji, M., Noguchi, H., Takeshita, S., Matsumoto, K., Nakamura, T., Higaki, J., Ogihara, T., 1999, Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension 33:1379-84). HGF/SF-containing implants in mouse subcutaneous tissue and rat cornea induce growth of new blood vessels from surrounding tissue. HGF/SF protein is expressed at sites of neovascularization including in tumors (Jeffers, M., Rong, S., Woude, G. F., 1996, Hepatocyte growth factor/scatter factor-Met signaling in tumorigenicity and invasion/metastasis. J. Mol. Med. 74:505-13; Moriyama, T., Kataoka, H., Koono, M., Wakisaka, S., 1999, Expression of hepatocyte growth factor/scatter factor and its receptor c-Met in brain tumors: evidence for a role in progression of astrocytic tumors Int. J. Mol. Med. 3:531-6). These findings suggest that HGF/SF plays a significant role in the formation and repair of blood vessels under physiologic and pathologic conditions. Further discussion of angiogenic proteins may be found in U.S. Pat. Nos. 6,011,009 and 5,997,868, both of which are incorporated herein by reference in their entireties.
Modulation of cellular proliferation by exogenously-supplied therapeutic agents has been offered as a new approach for the prophylaxis and/or treatment of various conditions and diseases in which limited cellular proliferation, or, in contrast, excessive proliferation of cells, is responsible for pathology, or at least for the prolongation of rebound from a pathological state to homeostasis. For example, the duration of wound healing, normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction, development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs, and vascularization of grafted or transplanted tissues, organs, or wound healing, may be accelerated by promoting cellular proliferation, particularly of vascular cells.
In other cases where abnormal or excessive cellular proliferation is the cause of pathology, such as in dysproliferative diseases including cancer, inflammatory joint and skin diseases such as rheumatoid arthritis, and neovascularization in the eye as a consequence of diabetic retinopathy, suppression of cellular proliferation is a desired goal in the treatment of these and other conditions. In either case, therapy to promote or suppress proliferation may be beneficial locally but not systemically, and for a particular duration, and proliferation modulating therapies must be appropriately applied.
In co-pending application Ser. No. 09/606,628, filed Jun. 29, 2000, incorporated herein by reference in its entirety, peptide mimetics with HGF/SF-like, proliferative activity and particularly angiogenic activity, as well as other agents, particularly peptide HGF/SF antagonists which inhibit cellular proliferation and, in particular, angiogenesis, were described. Such peptides have uses, for example, in the treatment of inflammatory diseases, cancer, neovascularization, cardiac ischemia, wound healing, and other conditions in which modulation of cellular proliferation including blood vessel growth is therapeutically beneficial, as described above.
It is toward the identification of small organic molecules with HGF/SF activity, or those that inhibit HGF/SF activity, that the present invention is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
In one broad aspect, the present invention is directed to methods for the modulation of hepatocyte growth factor/scatter factor (HGF/SF) activities in a mammal for the treatment of any of a number of conditions or diseases in which either HGF/SF has a therapeutically useful role, or in which the activity of endogenous HGF/SF is desirably inhibited or abrogated. Such modulation is achieved by the administration to the mammal of a compound of the invention in an amount effective to achieve the desired outcome. In one embodiment, the compounds of the invention modulate the activity of the HGF/SF receptor, c-Met. In a further embodiment, the compounds of the invention bind to c-Met.
In the instance where HGF/SF activity is desirable, certain compounds of the invention have been found to mimic or agonize the biological activities of HGF/SF, and thus are useful in the treatment, for example, of conditions or diseases in which enhanced cellular or vascular proliferation is desirable, among other desirable activities of HGF/SF. Such conditions or diseases include hepatic disease, renal disease, bone regeneration, hair growth, promoting wound or tissue healing, or augmenting or restoring blood flow to ischemic tissues such as the heart following myocardial infarction. Such compounds may be administered systemically or locally to particular tissues or organs, in order to achieve the desired systemic or local effect.
Such desirable activities also includes induction of proliferation of endothelial cells, induction of anti-apoptotic activity, induction of scatter activity, or any combination of the foregoing activities. In a preferred embodiment, any one of these activities is reduced or inhibited in the presence of exogenous c-Met receptor by a compound of the invention.
The compounds of the invention useful for mimicking or agonizing HGF/SF activity are characterized by being non-peptide, non-protein organic molecules with one or more of the activities of promoting proliferation of endothelial cells in vitro or in vivo, promoting angiogenesis in vitro or in vivo, increasing angiogenesis in wounds in vivo, promoting the growth of tumor cells in vitro or in vivo, promoting scatter, promoting anti-apoptotic activity, or inducing gene expression of angiogenic-cascade-related genes such as but not limited to IL-8 and angiopoietin-2. Preferred are
Goldberg Itzhak D.
Pillarisetti Sivaram
Klauber & Jackson
North Shore-Long Island Jewish Health System
Reamer James H.
LandOfFree
Small-molecule modulators of hepatocyte growth... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Small-molecule modulators of hepatocyte growth..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Small-molecule modulators of hepatocyte growth... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3048723