Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-29
2003-03-11
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S312000, C546S194000, C514S318000
Reexamination Certificate
active
06531494
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical agents which are &agr;
V
&bgr;
3
and/or &agr;
V
&bgr;
5
integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by &agr;
V
&bgr;
3
and/or &agr;
V
&bgr;
5
integrins.
BACKGROUND OF THE INVENTION
Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked &agr; and &bgr; polypeptide subunits. Currently eleven different &agr; subunits have been identified and six different &bgr; subunits have been identified. The various &agr; subunits can combine with various &bgr; subunits to form distinct integrins.
The integrin identified as &agr;
V
&bgr;
3
(also known as the vitronectin receptor) has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis (Ross, et al.,
J. Biol, Chem.,
1987, 262, 7703), Paget's disease, humoral hypercalcemia of malignancy (Carron et al.,
Cancer Res.
1998, 58, 1930), osteopenia (Lark et al.,
J Bone Miner Res.
2001, 16, 319), endometriosis (Healy et al.,
Hum. Reproductive Update,
1998, 4, 736), angiogenesis, including tumor angiogenesis (Cheresh,
Cancer Metastasis Rev.,
1991, 10, 3-10 and Brooks, et al.,
Cell,
1994, 79, 1157), retinopathy including macular degeneration (Friedlander et al.,
Proc. Natl. Acad. Sci USA
1996, 93, 9764), arthritis, including rheumatoid arthritis (Badger et al.,
Arthritis Rheum,
2001, 44, 128), periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis and artherosclerosis, (Brown et al.,
Cardiovascular Res.,
1994, 28, 1815). The compounds of the present invention are &agr;
V
&bgr;
3
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. Thus, compounds which selectively antagonize &agr;
V
&bgr;
3
would be beneficial for treating such conditions.
The integrin &agr;
V
&bgr;
5
plays a role in neovascularization. Antagonists of the &agr;
V
&bgr;
5
integrin will inhibit neovascularization and will be useful for treating and preventing angiogenesis metastasis, tumor growth, macular degeneration and diabetic retionopathy. M. C. Friedlander, et al.,
Science,
270, 1500-1502 (1995) disclose that a monoclonal antibody for &agr;
V
&bgr;
5
inhibits VEFG-induced angogenesis in the rabbit cornea and the chick chorioallantoic membrane model. Therefore, it would be useful to antagonize both the &agr;
V
&bgr;
5
and the &agr;
V
&bgr;
3
receptor. Such “mixed &agr;
V
&bgr;
5
/&agr;
V
&bgr;
3
antagonists” or “dual &agr;
V
&bgr;
3
/&agr;
V
&bgr;
5
antagonists” would be useful for treating or preventing angiogenesis, tumor metastasis, tumor growth, diabetic retinopathy, macular degeneration, atherosclerosis and osteoporosis.
It has been shown that the &agr;
V
&bgr;
3
integrin and other &agr;
V
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 &agr;
V
&bgr;
3
also bind to &agr;
V
&bgr;
5
, &agr;
V
&bgr;
1
and &agr;
IIb
&bgr;
3
. Antagonism of platelet &agr;
IIb
&bgr;
3
(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 &agr;
V
&bgr;
3
, it would be beneficial to develop compounds which are selective antagonists of &agr;
V
&bgr;
3
as opposed to &agr;
IIb
&bgr;
3
.
Further, it has not been established in the art that sparing &agr;
V
&bgr;
6
integrin would be a beneficial property to be incorporated in the design of antagonists of &agr;
V
&bgr;
3
. Rather, &agr;
V
&bgr;
6
has been identified as a target for antagonists because it is higly expressed in many carcinoma cell lines, and has been shown to enchance the proliferative capacity of a colon carcinoma cell line both in vivo and in vitro (Agrez et al., 1994,
J. Cell Biol.
127, 547). Additionally, &agr;
V
&bgr;
6
is expressed during the later stages of wound healing and remains expressed until the wound is closed (See Christofidou-Solomidou, et al., 1997
American J. of Pathol.,
151, 975), and therefore it is believed that &agr;
V
&bgr;
6
plays a role in the remodeling of the vasculature during the later stages of angiogenesis. Accordingly, antagonists of &agr;
V
&bgr;
6
are seen as useful in treating or preventing cancer by inhibiting tumor growth and metastasis (see, for example, U.S. Pat. No. 6,211,191).
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 &agr;
V
&bgr;
3
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 &agr;
V
&bgr;
3
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 &agr;
V
&bgr;
3
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 &agr;
V
&bgr;
3
provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of &agr;
V
&bgr;
3
antagonists causes dramatic regression of various histologically distinct human tumors.
The adhesion receptor integrin &agr;
V
&bgr;
3
was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells. Antagonists of &agr;
V
&bgr;
3
inhibit this process by selectively promoting apoptosis of cells in neovasculature. 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, &agr;
V
&bgr;
3
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 &agr;
V
&bgr;
3
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 results in osteoporosis (loss of bone), which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of &agr;
V
&bgr;
3
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 &agr;
V
&bgr;
3
leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide
Boys Mark L.
Chandrakumar Nizal S
Chen Barbara B.
Desai Bipinchandra N.
Devadas Balekudru
Aulakh Charanjit S.
Kovacevic Cynthia
Pharmacia Corporation
Polster Rachel
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