Propanoic acid derivatives

Details Propanoic acid derivatives Propanoic acid derivatives

1999-11-23

2001-11-20

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S269000, C544S214000, C544S215000, C544S242000, C544S243000, C544S333000, C544S335000

Reexamination Certificate

active

06319922

ABSTRACT:

This invention relates to a series of propanoic acid derivatives, to compositions containing them, to processes for their preparation and to their use in medicine.
Over the last few years it has become increasingly clear that the physical interaction of a cell with other cells or components of the extracellular matrix plays an important role in regulating its response to external stimuli such as chemotactic factors, growth factors, cytokines, and inflammatory mediators [Juliano and Haskill, J. Cell Biol. 1 577-585 (1993); Miyamoto et al J. Cell Biol. 135, 1633-1642 (1996)]. Furthermore, the physical attachment of cells to other cells or surfaces may be crucial for development of some normal physiological responses.
In many disease states normal physiological responses are inappropriately triggered and are detrimental to the well being of the host. Since adhesion molecules play a role in the physical interactions of cells, antagonists of adhesion molecules may be able to inhibit some of the detrimental biological responses found in many disease states.
The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in informing a cell about the nature of its extracellular environment is the integrin family. Members of this family are involved in helping to regulate processes such as proliferation, apoptosis, migration and gene expression in a range of different cell types. They have also been shown to play a key role in regulating immune and inflammatory responses.
The integrin family of cell surface adhesion molecules has a typical non-covalently linked heterodimer structure. At least 14 different integrin alpha chains and 8 different integrin beta chains have been identified [Sonnenberg A Current Topics in Microbiology and Immunology, 184 (1993)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in this field. Thus the integrin &agr;
v
&bgr;
3
consists of the alpha v chain non-covalently linked to the beta 3 chain.
Some integrin chains are capable of pairing with more than one partner. For example, the alpha v chain has also been reported to pair with the beta 1 chain, the beta 5 chain, the beta 6 chain and the beta 8 chain to give molecules which bind to different sets of ligands and which are referred to respectively as the integrins &agr;
v
&bgr;
1
, &agr;
v
&bgr;
5
, &agr;
v
&bgr;
6
and &agr;
v
&bgr;
8
.
Integrins containing the &agr;
v
subunit form a family of integrins which generally (but not always) bind to vitronectin although several of them will bind to a range of other matrix molecules and/or cell surface molecules. For example &agr;
v
&bgr;
3
will bind to molecules such as vitronectin, fibronectin, fibrinogen, osteopontin, bone sialoprotein, thrombospondin, pro von Willebrand factor and CD31.
The importance of integrin function in normal physiological responses is highlighted by two human deficiency diseases in which integrin function is defective. Thus, in the disease termed Leukocyte Adhesion Deficiency (LAD) there is a defect in one of the families of integrins expressed on leukocytes. Patients suffering from this diesease show a dramatically reduced ability to recruit leukocytes to inflammatory sites. In the case of patients suffering from the disease termed Glanzman's thrombasthenia (a defect in a member of the beta 3 integrin family) there is a defect in blood clotting.
The interaction of cells with components of the extracellular environment via receptors containing &agr;
v
has been reported to be involved in a number of cellular responses which may be important in human disease states. These include endothelial cell proliferation and angiogenesis [Friedlander M, et al, Science 270, 1500-1502 (1995)], coronary smooth muscle cell migration, proliferation and extracellular matrix invasion [Panda, D., PNAS, 94, 9308-9313 (1997)], regulation of other integrin molecules on different cell types [Blystone, S D. J. Cell Biol. 127, 1129-1137 (1994); Imhof, B. Eur. J. Immunol, 27, 3242-3252 (1997)] and bone resorption [Ross F. P. et al, J. Biol. Chem. 268 9901-9907 (1993)]. Furthermore, the &agr;
v
receptor has been reported to bind to the protease MMP-2 and this may also modify cell function [Brooks P.C. et al, Cell, 92, 391-400 (1998)].
Monoclonal antibodies and peptides have also been used to demonstrate in animal models that potentially beneficial changes in physiology can be achieved by blocking the function of &agr;
v
-containing integrin receptors. For example, Mitjans F. et al [Journal of Cell Science, 108, 2825-2838 (1995)] showed that in a mouse model an antibody that bound to the &agr;
v
chain inhibited tumour development and metastasis. Brooks P.C., et al; [J. Clin. Invest. 96, 1815-1822 (1995)] demonstrated that an antibody that blocked the function of &agr;
v
&bgr;
3
inhibited the growth of a tumour implanted into a piece of human skin grafted on to a SCID mouse. Christofidou-Solomidou M, [Am. J. Pathol. 151, 975-983 (1997)] has reported that an anti-&agr;
v
monoclonal antibody inhibited angiogenesis at the site of wound healing. Hammes H-P, et al, [Nature Medicine, 2, 529-533 (1996)] showed that an &agr;
v
integrin antagonist cyclic peptide inhibited retinal neovascularisation in a model which may have relevance to the human disease states of retinopathy and senile macular degeneration. Srivata S, et al [Cardiovascular Research 36 408-428 (1997)] have reported that in an animal model a peptidic &agr;
v
&bgr;
3
antagonist can limit neointimal hyperplasia and luminal stenosis.
&agr;
v
&bgr;
3
has been reported to bind to a molecule expressed on endothelial cells termed CD31 [Piali L. et al, J. Cell Biol. 130, 451-460 (1995)]. Thus &agr;
v
&bgr;
3
may play a role in leukocyte extravasation. It has also been shown to be capable of co-stimulating T-cell degranulation [Ybarrondo B. Immunology, 91, 186-192 (1997)]. Inhibition of &agr;
v
function may down regulate immune and/or inflammatory responses.
&agr;
v
&bgr;
3
has also been shown to play a role in the ingestion of apoptotic cells by macrophages [Akbar A. N. et al, J. Exp. Med 180, 1943-1947 (1994)]. The rapid phagocytosis of apoptotic cells may be a physiological method of reducing inflammatory responses associated with cell lysis. The modulation of &agr;
v
&bgr;
3
function may alter the inflammatory responses mounted in regions of apoptosis. In some disease states this may be beneficial.
It has also been shown that members of the &agr;
v
family play a key role in the ability of osteoclasts to resorb bone. An imbalance between bone formation and resorption can lead to major health problems. Blockade of &agr;
v
containing receptors can inhibit bone resorption in an animal model [Engleman V. W. et al J. Clin. Invest. 99, 2284-2292, (1997)] and this suggests that &agr;
v
antagonists may be useful in the treatment of human diseases such as osteoporosis, Paget's disease, humoral hypercalcaemia of malignancy and metastic bone disease.
&agr;
v
containing receptors are often upregulated at sites of angiogenesis where this occurs for example in tumours, and some pathological conditions. Arap W, et al [Science, 279, 377-380, (1998)] have shown that peptides that bind to &agr;
v
containing receptors can be used to deliver drugs to such sites and an antibody recognising an &agr;
v
integrin has been shown to be capable of imaging tumour vasculature [Sipkins D. A. et al Nature Medicine, 4, 623-626 (1998].
The tissue distribution and range of ligands of different members of the &agr;
v
integrin family suggests that these molecules may have different physiological roles. This view is supported by Friedlander M et al [Science, 27, 1500-1502, (1995)] who showed that angiogenesis associated with

Affiliated with

Also associated with

Rating

Propanoic acid derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Propanoic acid derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Propanoic acid derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2583316