WO2007076055A2 - Compositions and methods comprising proteinase activated receptor antagonists - Google Patents
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Abstract
Compositions and methods comprising proteinase activated receptor antagonists are provided. More particularly, the present invention relates to the use of proteins, peptides and molecules that bind to proteinase activated receptor 2, and inhibit the processes associated with the activation of that receptor. More specifically, the present invention provides novel compositions and methods for the treatment of disorders and diseases such as those associated with abnormal cellular proliferation, angiogenesis, inflammation and cancer.
Description
COMPOSITIONS AND METHODS COMPRISING PROTEINASE ACTIVATED RECEPTOR ANTAGONISTS
CROSS REFERENCE TO RELATED PATENT APPLICATIONS
The present application claims priority to United States Provisional Application Serial No. 60/753,363 filed December 22, 2005.
FIELD OF THE INVENTION
The present invention relates to compositions and methods comprising proteinase activated receptor antagonists. More particularly, the present invention relates to the use of proteins, peptides and non- peptide molecules that bind to proteinase activated receptors, and inhibit the processes associated with the activation of that receptor. More specifically, the present invention provides novel compositions and methods for the treatment of disorders and diseases such as those associated with abnormal cellular proliferation, angiogenesis, inflammation and cancer.
BACKGROUND OF THE INVENΗON
Cellular proliferation is a normal ongoing process in all living organisms and is one that involves numerous factors and signals that are delicately balanced to maintain regular cellular cycles. The general process of cell division is one that consists of two sequential processes: nuclear division (mitosis), and cytoplasmic division (cytokinesis).
Because organisms are continually growing and replacing cells, cellular proliferation is a central process that is vital to the normal functioning of almost all biological processes. Whether or not mammalian cells will grow and divide is determined by a variety of feedback control
mechanisms, which include the availability of space in which a cell can grow, and the secretion of specific stimulatory and inhibitory factors in the immediate environment.
When normal cellular proliferation is disturbed or somehow disrupted, the results can affect an array of biological functions.
Disruption of proliferation could be due to a myriad of factors such as the absence or overabundance of various signaling chemicals or presence of altered environments. Some disorders characterized by abnormal cellular proliferation include cancer, abnormal development of embryos, improper formation of the corpus luteum, difficulty in wound healing as well as malfunctioning of inflammatory and immune responses.
Cancer is characterized by abnormal cellular proliferation. Cancer cells exhibit a number of properties that make them dangerous to the host, often including an ability to invade other tissues and to induce capillary ingrowth, which assures that the proliferating cancer cells have an adequate supply of blood. One of the defining features of cancer cells is that they respond abnormally to control mechanisms that regulate the division of normal cells and continue to divide in a relatively uncontrolled fashion until they kill the host. Angiogenesis and angiogenesis related diseases are closely affected by cellular proliferation. As used herein, the term "angiogenesis" means the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans or animals undergo angiogenesis only in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonic development and formation of the corpus luteum, endometrium and placenta. The term "endothelium" is defined herein as a thin layer of flat cells that lines serous cavities, lymph vessels, and blood vessels. These cells are defined herein as "endothelial cells". The term "endothelial inhibiting activity" means the capability of a molecule to inhibit angiogenesis in general. The
inhibition of endothelial cell proliferation also results in an inhibition of angiogenesis.
Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a "sprout" off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel.
Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, tumor metastasis and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions. The diverse pathological disease states in which unregulated angiogenesis is present have been grouped together and named, "angiogenic-dependent", "angiogenic-associated", or "angiogenic-related" diseases. These diseases are a result of abnormal or undesirable cell proliferation, particularly endothelial cell proliferation.
The hypothesis that tumor growth is angiogenesis-dependent was first proposed in 1971 by Judah Folkman (N. Engl. Jour. Med. 285:1182 1186, 1971). In its simplest terms the hypothesis proposes that once tumor "take" has occurred, every increase in tumor cell population must be preceded by an increase in new capillaries converging on the tumor. Tumor "take" is currently understood to indicate a prevascular phase of tumor growth in which a population of tumor cells occupying a few cubic millimeters volume and not exceeding a few million cells, survives on existing host microvessels. Expansion of tumor volume beyond this phase requires the induction of new capillary blood vessels. For example,
pulmonary micrometastases in the early prevascular phase would be undetectable except by high power microscopy on histological sections. Further indirect evidence supporting the concept that tumor growth is angiogenesis dependent is found in U.S. Patent Nos. 5,639,725, 5,629,327, 5,792,845, 5,733,876, and 5,854,205, all of which are incorporated herein by reference.
Thus, it is clear that cellular proliferation, particularly endothelial cell proliferation, and most particularly angiogenesis, plays a major role in the metastasis of a cancer. If this abnormal or undesirable proliferation activity could be repressed, inhibited, or eliminated, then the tumor, although present, would not grow. In the disease state, prevention of abnormal or undesirable cellular proliferation and angiogenesis could avert the damage caused by the invasion of the new microvascular system. Therapies directed at control of the cellular proliferative processes could lead to the abrogation or mitigation of these diseases.
Recently, studies have been conducted that correlate proteinase activated receptor activation with certain disorders and diseases. Of particular interest is proteinase activated receptor-2 which has been discovered to be associated with disorders such as inflammation, angiogenesis, and sepsis. Although several attempts have been made, no effective antagonists of proteinase activated receptor-2 have been identified.
What is needed are compositions and methods that can inhibit abnormal or undesirable cellular function, especially functions that are associated with undesirable cellular proliferation, angiogenesis, inflammation and cancer. The compositions should comprise proteins, peptides or non-peptide molecules that overcome the activity of endogenous proteinase activated receptor ligands and prevent the activation of proteinase activated receptors thereby inhibiting the development of abnormal physiological states associated with inappropriate proteinase activated receptor activation. Finally, the
compositions and methods for inhibiting proteinase activated receptor activation should preferably be non-toxic and produce few side effects.
SUMMARY OF THE INVENTION Compositions and methods are provided that are effective in inhibiting abnormal or undesirable cell function, particularly cellular activity and proliferation related to angiogenesis, neovascularization, inflammation, tumor growth, sepsis, neurogenic and inflammatory pain, asthma and post operative ileus. The compositions comprise a naturally occurring or synthetic protein, peptide, protein fragment or non-peptide molecule containing or mimicking the action of all or an active portion of a ligand that binds proteinase activated receptors, optionally combined with a pharmaceutically acceptable carrier.
Representative ligands or antagonists useful for the present invention comprise proteins, peptides and molecules that bind proteinase activated receptors, such as, but not limited to, proteinase activated receptor 1 (PAR-I), proteinase activated receptor 2 (PAR-2), proteinase activated receptor 3 (PAR-3), or proteinase activated receptor 4 (PAR-4). Preferably, the protein, peptide, protein fragment or molecule of the present invention contains or mimics the action of all or an active portion of the ligands and antagonists that bind the above identified receptors. The term "active portion", as used herein, means a portion of a protein, peptide or molecule that inhibits proteinase activated receptor activation. Also included in the present invention are homologs, peptides, protein fragments, or combinations thereof of the ligands and antagonists, that inhibit proteinase activated receptor activity.
Though not wishing to be bound by the following theory, it is believed that by inhibiting proteinase activated receptor activity, the methods and compositions described herein are useful for inhibiting diseases and disorders associated with abnormal proteinase activated receptor activity. The methods provided herein for treating diseases and
processes mediated by proteinase activated receptors, such as inflammation and cancer, involve administering to a human or animal the composition described herein in a dosage sufficient to inhibit proteinase activated receptor activity, particularly PAR-2 activity. The methods are especially useful for treating or repressing the growth of tumors, particularly by inhibiting angiogenesis and for reducing inflammation and inflammatory responses.
Accordingly, it is an object of the present invention to provide methods and compositions for treating diseases and processes that are mediated by abnormal or undesirable proteinase activated receptor activity.
Another object of the present invention is to provide methods and compositions for inhibiting abnormal or undesirable cell function, cellular activity and proliferation particularly related to angiogenesis, neovascularization, inflammation, conditions related to inflammation, tumor growth, tumor metastasis, sepsis, neurogenic and inflammatory pain, asthma and post operative ileus.
It is another object of the present invention to provide methods and compositions for treating or repressing the growth of a cancer or a tumor metastasis.
It is yet another object of the present invention to provide methods and compositions for therapy of cancer that has minimal side effects.
It is another object of the present invention to provide methods and compositions for treating diseases and processes that are mediated by angiogenesis.
It is another object of the present invention to provide methods and compositions for treating or repressing inflammation, inflammatory responses and inflammatory diseases.
It is yet another object of the present invention to provide methods and compositions for therapy of inflammation that has minimal side effects.
It is another object of the present invention to provide methods and compositions for treating diseases and processes that are mediated by inflammation or inflammatory responses, including, but not limited to, acute inflammation, chronic inflammation, rheumatoid arthritis, dermatitis, inflammatory bowel disease, inflammatory bowel syndrome, asthma, sepsis, neurogenic pain, and dermatitis.
Yet another object of the present invention is to provide methods and compositions comprising the use of proteins, peptides, molecules, active fragments and homologs thereof that inhibit proteinase activated receptor activity.
Another object of the present invention is to provide methods and compositions for treating diseases and processes that are mediated by angiogenesis by administrating antiangiogenic compounds comprising ligands that inhibit proteinase activated receptor activity. It is a further object of the present invention to provide methods and compositions for treating diseases and processes that are mediated by abnormal proteinase activated receptor activity.
It is another object of the present invention to provide methods and compositions for diagnosing diseases and disorders by measuring abnormal proteinase activated receptor activity.
It is still another object of the present invention to provide compositions comprising ligands that bind proteinase activated receptors wherein the compositions further comprise pharmaceutically acceptable carriers. Yet another object of the present invention is to provide methods and compositions comprising ligands that bind proteinase activated receptors wherein the compositions further comprise pharmaceutically acceptable carriers that may be administered intranasal, intramuscularly, intravenously, transdermally, orally, topically, vaginally, rectally, or subcutaneously.
It is yet another object of the present invention to provide compositions and methods for treating diseases and processes that are mediated by angiogenesis including, but not limited to, hemangioma, solid tumors, blood borne tumors, leukemia, tumor metastasis, telangiectasia, psoriasis, scleroderma, pyogenic granuloma, myocardial angiogenesis, atherosclerosis, Crohn's disease, plaque neovascularization, arteriovenous malformations, corneal diseases, rubeosis, neovascular glaucoma, diabetic retinopathy, retrolental fibroplasia, arthritis, diabetic neovascularization, macular degeneration, wound healing, peptic ulcer, Helicobacter related diseases, fractures, keloids, vasculogenesis, hematopoiesis, endometriosis, ovulation, menstruation, placentation, and cat scratch fever.
These and other objects, features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiment and the appended claims.
BRIEF DESCRIPTION OF THE HGURES
Figure 1 provides a schematic showing a proposed interaction of an antagonist with activated PAR τeceptor.
DETAILED DESCRIPTION
The following description includes the best presently contemplated mode of carrying out the invention. This description is made for the purpose of illustrating the general principles of the inventions and should not be taken in a limiting sense. The entire text of the references mentioned herein are hereby incorporated in their entireties by reference, including United States Provisional Application Nos. 60/391,655 filed June 26, 2002, 60/398,662 filed July 26, 2002, 60/458,095 filed March 27, 2003, 60/466,296 filed April 29, 2003, 60/603,307 filed August 20, 2004, and 60/644,710 filed January 18, 2005, as well as United States Patent Application Serial Nos. 10/608,886 filed June 26, 2003, 10/833,252 filed
April 27, 2004, and 11/208,460 filed August 19, 2005. Also incorporated
by reference herein is United States Provisional Application Nos. 60/753,363 filed December 22, 2005.
Proteinase activated receptor-2 (PAR-2) is a seven transmembrane G-protein coupled receptor (GPCR) which signals in response to the proteolytic activity of trypsin, tryptase, matriptase, the tissue factor (TF)/ factor Vila (fVIIa) complex and other proteases, including, but not limited to, neutrophil protease-3. Proteolytic cleavage of the amino terminus results in the unveiling of a new amino terminus that activates the receptor through a tethered peptide ligand mechanism; essentially the new terminus becomes the ligand which inserts into the ligand binding pocket of the receptor. The short synthetic activating peptide (known variously as AP2 or P2AP or P2P), SLIGKV (ENMD-1003) (human) (SEQ ID NO: 1), SLIGRL-NH2 (mouse) (SEQ ID NO: 2) activates the receptor. Upon binding of the ligand, there is an increase in intracellular calcium concentration indicating activation of the receptor.
Several studies have demonstrated that PAR-2 is involved in angiogenesis, neovascularization and inflammation. PAR-2 has also been associated with pain transmission, tissue injury and regulation of cardiovascular function. For example, Milia et al. discuss the wide expression of PAR-2 in the cardiovascular system, mediation of endothelial cell mitogenesis in vitro by PAR-2, and promotion of vasodilation and microvascular permeability in vivo by PAR-2: all of these steps are regarded as essential steps; in angiogenesis. (Milia et al. Circulation Research Vol. 91 (4) 2002 pp.346-352, which is incorporated . herein by reference in its entirety). Milia et al. further discuss upregulation of PAR-2 expression by cytokines, including tumor necrosis factor-a, interleukin-b, and lipopolysaccharide, all thought to be involved in inflammation (ibid). !
In addition, recent studies have shown that PAR-2 activation mediates neurogenic inflammation and nociception, illustrating that in some cases, activation of PAR-2 on neurons leads to the generation of
proinflammatory cytokines, and a panoply of inflammatory signals. PAR- 2 has also been shown to play an essential role in the onset of chronic inflammatory diseases such as rheumatoid arthritis.
Based on the current knowledge of PAR activity in abnormal physiological states, it is believed that PAR activity, and in particular
PAR-2 activity, is associated with numerous disorders and diseases including, but not limited to, angiogenesis, neovascularization, inflammation, tumor growth, sepsis, neurogenic and inflammatory pain, asthma and post operative ileus. It has previously been shown that the proteolytic activity of the
PAR-2 agonist TF/fVIIa promotes tumor growth and angiogenesis independently of its role in coagulation (Hembrough et al, Blood 103:3374-3380). Further characterization and analysis of the role of PAR- 2 and its involvement in disease has been difficult, because until now, no specific antagonists of PAR-2 had been identified. Here we describe specific antagonists of PAR-2 signaling. In vivo, these PAR-2 antagonists are inhibitors of angiogenesis, tumor growth and inflammatory diseases. Since previous studies by the inventors suggested a role for PAR-2 in tumor growth and angiogenesis, these inhibitors were further assessed to determine if they could inhibit tumor growth or angiogenesis. In vivo treatment with these PAR-2 inhibitors results in inhibition of both angiogenesis and tumor growth. Thus, these inhibitor studies demonstrate that PAR-2 activity plays a role in regulating angiogenesis and tumor growth. These data describing potent and specific antagonists of PAR-2 signaling promise to be powerful tools for the study of PAR-2 physiology in normal and pathological processes and for amelioration of disease processes mediated by PAR-2.
Numerous reports have been published demonstrating important physiological functions of PAR-2. These activities include nociception, acute and chronic inflammation, dermatitis, rheumatoid arthritis, asthma, and neurogenic pain. In each of these studies mention is made of the need
for specific PAR-2 antagonists and their great value in the future characterization of this receptor. Until the present discovery, there has existed a serious unmet need for effective PAR antagonists.
Although other studies claim to describe methods that involve inhibiting PAR-2 activity, none of them actually identify specific antagonists. For example, one such study focuses instead on blocking proteolytic cleavage of the PAR-2 amino terminal by trypsin, tryptase, matriptase or the tissue factor (TF)/ factor Vila (fVIIa) complex (see for example WO 01/52883 Al). Such studies acknowledge the need for PAR- 2 antagonists, but fail to define any specific inhibitors or provide any guidance with regard to potential structures for such peptides, proteins or molecules. The present inventors have successfully identified specific inhibitors of PAR-2, as well as certain protein/peptide structures that enable the design and elucidation of PAR-2 antagonists. The present invention generally comprises the compounds set forth in Table 1
(beginning on page 30), ENMD23-0001-ENMD23-814.
The present invention is generally related to compositions and methods for modifying the activity of proteinase activated receptors comprising the administration of proteinase activated receptor ligands, antagonists, enantiomers, racemates, active fragments, pharmaceutically acceptable salts and prodrugs, wherein the ligands, antagonists, enantiomers, racemates, active fragments, pharmaceutically acceptable salts and prodrugs, comprise compounds selected from the group consisting of ENMD23-0001-ENMD23-0814 (see Table 1). In certain embodiments, the proteinase activated receptor comprises PAR-I, PAR-2,
PAR-3 and PAR-4, and in certain preferred embodiments, the proteinase activated receptor comprises PAR-2. The compositions may be optionally combined with pharmaceutically acceptable excipients, carriers or sustained release matrices.
The present invention is further related to compositions and methods for treating humans or animals having undesirable cellular proliferation, cancer or inflammation comprising administering to the human or animal a composition comprising proteinase activated receptor ligands, antagonists, enantiomers, racemates, active fragments, pharmaceutically acceptable salts and prodrugs, wherein the ligands, antagonists, enantiomers, racemates, active fragments, pharmaceutically acceptable salts and prodrugs comprise compounds selected from the group consisting of ENMD23-0001-ENMD23-0814 (see Table 1). In certain embodiments, the proteinase activated receptor comprises PAR 1,
PAR 2, PAR 3 and PAR 4, and in certain preferred embodiments, the proteinase activated receptor comprises PAR 2. The compositions may be optionally combined with pharmaceutically acceptable excipients, carriers or sustained release matrices. In certain embodiments, the undesirable cellular proliferation in the human or animal occurs during angiogenesis- related disease. In certain specific situations, the undesirable cellular proliferation is associated with atherosclerosis, solid tumors; blood-borne tumors, such as leukemias; tumor metastasis; benign tumors, hemangiomas, acoustic neuromas, neurofibromas, trachomas, pyogenic granulomas, vascular malfunctions, abnormal wound healing, inflammatory, immune disorders, Behcet's disease, gout, gouty arthritis, abnormal angiogenesis accompanying rheumatoid arthritis, skin diseases, psoriasis, diabetic retinopathy, ocular angiogenic diseases, retinopathy of prematurity, retrolental fibroplasia, macular degeneration, corneal graft rejection, neovascular glaucoma, liver diseases or Oster Webber Syndrome
(Osler-Weber-Rendu disease).
The compositions of the present invention may be administered orally, topically, implanted locally, implanted for systematic release, implanted for sustained release, implanted in a biodegradable particle, subcutaneously, intravenously, intra-arterially, intraocularly, transdermally, or transbuccally.
As discussed above, PARs are a family of GPCRs that function as sensors of thrombotic or inflammatory proteinase activity. Knockout mice lacking the PAR-2 receptor demonstrated little joint swelling or tissue damage in an adjuvant monoarthritis model of chronic inflammation, thereby confirming the role of PAR-2 in inflammation. In another experiment, the inventors showed that the tissue factor coagulation pathway was required for the growth of both primary and metastatic tumors. This required the activity of TF/fVIIa complex, but not fXa, which is the normal, physiological target of TF/fVIIa activity. Accordingly, though not wishing to be bound by the following theory, it is believed that in abnormal physiological states, the TF/fVIIa complex is targeting something other than fXa, and based on the studies herein, the inventors believe that the target is PAR-2.
The processes by which these changes are made to molecules of interest are well known to those skilled in the fields of medicinal chemistry, drug discovery, and drug development, and include, but are not limited to, combinatorial and parallel chemistry, medicinal chemistry, in silico modeling, computer-aided drug design, in silico modeling of absorption, distribution, metabolism, elimination or toxicology, and modeling using predictive techniques including, but not limited to, in silico pharmacophores, QSAR and CoMFA.
The methods by which improvements in or modifications to properties of molecules are measured or tested are well known to those skilled in the fields of medicinal chemistry, drug design, drug development, toxicology, physiology and pharmacology. Examples of these methods include, but are not limited to, PAMPA or CaCo2 assessment of permeability; in vivo, in vitro, and ex vivo testing of pharmacology including, but not limited to, receptor activation and/or signaling, reduction in angiogenesis, tumor growth, tumor metastasis, or inflammation; in vivo, in vitro or ex vivo testing of binding; in vivo, in vitro, and ex vivo assessment of toxicology; in vitro metabolism assays
using cells, cell extracts, or isolated ' drug metabolism enzymes; in vivo determinations of absorption, distribution, metabolism, elimination or toxicology; cardiac toxicity testing using KERG ion channel assays; formulation studies; and pre-clinical and clinical evaluations in humans or other animal species.
The moieties or components of the PAR antagonists can be assembled using a number of synthetic approaches using appropriate protecting groups. Approaches for linking moieties or components include but are not limited to amides, amines, C-C bonds, ethers, and esters. These approaches are given as examples only, and are not limiting. These and other approaches are well known tb those skilled in the art of organic chemistry, medicinal chemistry or drug design. For example, where the components are linked by an amide functionality, peptide or amide coupling reactions can be used. Such coupling reagents include, but are not limited to, 1,3-dicyclohexyl carbodiimide, l-ethyl-3-(3- dimethylaminopropyl)-carbo-diimide, 1-hydroxy-benzotriazole and N,N- diisopropylethyl amine or carbonyl diimidizole. Attachments to carbocyclic or heterocyclic rings can be accomplished by use of enolate or Wittig type chemistry using the appropriate carbonyl precursors. Heterocycles including pyrazoles can be formed with desired substitutions in place through cyclization reactions such as described by Stauffer et al., in Bioorganic and Medicinal Chemistry, volume 9, pages 141-150 (2001) which is incorporated herein by reference in its entirety. Several of the heterocycles can be synthesized by coupling the appropriately substituted precursors to generate the heterocyclic ring (March and Smith, Advanced
Organic Chemistry, Wiley Interscience, New York, NY, 2001; Sainsbury, Malcom, Heterocyclic Chemistry, Royal Society of Chemistry, Cambridge, UK, 2001; Davies, D, Aromatic Heterocyclic Chemistry, Oxford University Press, Oxford, UK, 2004; Jie Jack Lie, Ed., Name Reactions in Heterocyclic Chemistry, Wiley, New York, NY, 2004), all of which are incorporated herein by reference in their entirety. These and
other texts and the chemical literature can also be used to aid in functionalizing existing caτbocyclic or heterocyclic rings. Grignard or lithium, reagents can be prepared to couple components together via halogen substituted moieties. Aromatic halogens can also undergo Friedel-Crafts acylations or alkylations to give coupled heterocycles.
Many name reactions that can be used to couple the individual components are known to those skilled in the art and are listed in texts such as: March and Smith, Advanced Organic Chemistry, Wiley Interscience, New York, NY, 2001; Carey and Sundburg, Advanced Organic Chemistry, Part B: Reactions and Synthesis, Fourth , Ed., Kluwer Academic/Plenum
Publishing, New York, NY 2001; Jie Jack Li, Name Reactions, Springer, New York, NY, 2002; Hassner and Stumer, Organic Synthesis Based on Name Reactions, Second Ed., Pergamon Press, New York, NY, 2002; and Mundy and Ellerd, Name Reactions and Reagents in Organic Synthesis, Wiley Interscience, New York, NY, 1988, all of which are incorporated herein by reference in their entirety. Those skilled in the art understand that various protection groups can be used to ensure the synthesis of the desired product Protection groups commonly used include, but are not limited to, ester, amide, carbamate, benzyl, t-Boc, trityl, and Cbz groups and are described in texts including Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed. Wiley Interscience, New York, NY, 1999, and Kocienski, Protective Groups, 3rd Ed. Verlag, NY, NY 2003, all of which are incorporated herein by reference in their entirety. It is well understood by those skilled in the art that acids and bases can be prepared either as salts or in un-ionized forms (conjugate acids or bases). A variety of pharmacologically and pharmaceutically known and accepted salts can be prepared and are envisioned by this invention.
In accordance with the methods of the present invention, the compositions and methods described herein, containing a protein, peptide, protein fragment, or molecule including all or an active portion of a ligand that inhibits PARs, optionally in a pharmaceutically acceptable carrier, is
administered to a human or animal in an amount sufficient to inhibit undesirable cell proliferation, particularly endothelial cell proliferation, angiogenesis or an angiogenesis-related disease, such as cancer, inflammation, inflammatory processes or inflammatory diseases.
Definitions
The terms "a", "an" and "the" as used herein are defined to mean one or more and include the plural unless the context is inappropriate.
As used herein, the phrase "proteinase activated receptor" is defined to encompass all proteinase activated receptors (PARs), including, but not limited to, PAR-I, PAR-2, PAR-3 and PAR-4.
The term "antagonist" is used herein to define a protein, peptide or molecule that inhibits proteinase activated receptor activity.
The term "active portion" is defined herein as the portion of a ligand or molecule necessary for inhibiting the activity of proteinase activated receptors. The active portion has the ability to inhibit proteinase activated receptors as determined by in vivo or in vitro assays or other known techniques.
The term "mimetic" is generally defined as a compound that mimics a biological material in its structure or function.
The term peptidomimetic is generally defined as a compound containing non-peptidic structural elements capable of mimicking or antagonizing the biological action(s) of a natural parent peptide.
The term "peptides" describes chains of amino acids (typically L- amino acids) whose alpha carbons are linked through peptide bonds formed by a condensation reaction between the carboxyl group of the alpha carbon of one amino acid and the amino group of the alpha carbon of another amino acid. In naturally occurring peptides, in most cases, the terminal amino acid at one end of the chain {i.e., the amino terminal) has a free amino group, while the terminal amino acid at the other end of the chain (i.e., the carboxy terminal) has a free carboxyl group. As such, the
term "amino terminus" (abbreviated N-terminus) refers to the free alpha- amino group on the amino acid at the amino terminal of the peptide, or to the alpha-amino group (amido group when participating in a peptide bond) of an amino acid at any other location within the peptide. Similarly, the term "carboxy terminus" (abbreviated C-terminus) refers to the free carboxyl group on the amino acid at the carboxy terminus of a peptide, or to the carboxyl group of an amino acid at any other location within the peptide.
Typically, the amino acids making up a peptide are numbered in order, starting at the amino terminal arid increasing in the direction toward the carboxy terminal of the peptide. Thus, when one amino acid is said to "follow" another, that amino acid is positioned closer to the carboxy terminal of the peptide than the preceding amino acid. Here, naturally occurring amino acids are represented in the text by the commonly used one letter codes (e.g. G = glycine).
The term "residue" is used herein to refer to an amino acid (D or L enantiomer) that is incorporated into a peptide by an amide bond. As such, the amino acid may be a naturally occurring amino acid or, unless otherwise limited, may encompass known analogs of natural amino acids that function in a manner similar to the naturally occurring amino acids
(Le., amino acid mimetics). Moreover, an amide bond mimetic includes peptide backbone modifications well known to those skilled in the art.
Furthermore, one skilled in the art will recognize that, as mentioned above, individual substitutions, deletions or additions which alter, add or delete a single amino acid or several amino acids in a sequence are conservatively modified variations where the alterations result in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. The following six groups each contain examples of amino acids that are frequently considered as conservative substitutions for one another:
1) Alanine (A), Serine (S), Threonine (T);
2) Aspartic acid (D), Glutamic acid (E);
3) Asparagine (N), Glutamϊne (Q);
4) Arginine (R), Lysine (K); Glutamine (Q); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);
6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W). Typically, the isolated, antiproliferative peptides described herein are at least about 80% puτe5 usually at least about 90%, and preferably at least about 95% as measured by HPLC. When peptides are relatively short in length (i.e., less than about 50 amino acids), they are often synthesized using chemical peptide synthesis • techniques. Solid phase synthesis is a method in which the C-teπniπal amino acid of the sequence is attached to an insoluble support followed by sequential addition of the remaining amino acids in the sequence. This is a preferred ' method for the chemical synthesis of the peptides described herein. Techniques for solid phase synthesis are known to those skilled in the art.
Short peptides and related amides can also by synthesized efficiently by solution phase coupling chemistry. Amino acids and related molecules, with the appropriate protection groups, are coupled in solution to yield amides and peptides. Coupling reagents for forming amide bonds include, but are not limited to, l;3-dicyclohexyl carbodiimide, 1- hydroxybenzotriazole and N,N-diisopropylethyl amine or carbonyl diimidizole. As employed herein, the phrase "biological activity" refers to the functionality, reactivity, and specificity of compounds that are derived from biological systems or those compounds that are reactive to them, or other compounds that mimic the functionality, reactivity, and specificity of these compounds. Examples of suitable biologically active compounds include, but are not limited to, enzymes, antibodies, antigens and proteins.
The term "bodily fluid," as used herein, includes, but is not limited to, saliva, gingival secretions, cerebrospinal fluid, gastrointestinal fluid, mucous, urogenital secretions, synovial fluid, blood, serum, plasma, urine, cystic fluid, lymph fluid, ascites, pleural effusion, interstitial fluid, intracellular fluid, ocular fluids, seminal fluid, mammary secretions, vitreal fluid, and nasal secretions.
The inhibitory proteins and peptides of proteinase activated receptors of the present invention may be isolated from body fluids including, but not limited to, serum, urine, and ascites, or may be synthesized by chemical or biological methods, such as cell culture, recombinant gene expression, and peptide synthesis. Recombinant techniques include gene amplification from DNA sources using the polymerase chain reaction (PCR), and gene amplification from RNA sources using reverse transcriptase/PCR. Ligands of interest can be extracted from body fluids by known protein extraction methods, particularly the method described by NoVotny, W.F., et al., J. Biol. Chem. 264:18832-18837 (1989).
Formulations The naturally occurring or synthetic protein, molecule, peptide, or protein fragment, containing all or an active portion of a protein, peptide or molecule that may bind to a proteinase activated receptor can be prepared in a physiologically acceptable formulation, such as in a pharmaceutically acceptable carrier, using known techniques. For example, the protein, peptide, protein fragment or non-peptide molecule is combined with a pharmaceutically acceptable excipient to form a therapeutic composition.
Alternatively, the gene for the protein, peptide, or protein fragment, containing all or an active portion of a desired ligand, may be delivered in a vector for continuous administration using gene therapy techniques. The
vector may be administered in a vehicle having specificity for a target site, such as a tumor.
The composition may be in the form of a solid, liquid or aerosol. Examples of solid compositions include pills, creams, and implantable dosage units. Pills may be administered orally. Therapeutic creams may be administered topically. Implantable dosage units may be administered locally, for example, at a tumor site,' or may be implanted for systematic release of the therapeutic composition, for example, subcutaneously. Examples of liquid compositions , include formulations adapted for injection subcutaneously, intravenously, intra-arterially, and formulations for topical and intraocular administration. Examples of aerosol formulations include inhaler formulations for administration to the lungs. Also envisioned are other compositions for administration including, but not limited to, suppositories, transdermal, transbuccal, and ocular administration.
The composition may be administered by standard routes of administration. In general, the composition may be administered by topical, oral, rectal, nasal or parenteral (for example, intravenous, subcutaneous, or intermuscular) routes. In addition, the composition may be incorporated into sustained release matrices such as biodegradable polymers, the polymers being implanted in the vicinity of where delivery is desired, for example, at the site of a tumor or site of inflammation. The method includes administration of a single dose, administration of repeated doses at predetermined time intervals, and sustained administration for a predetermined period of time. Examples of biodegradable polymers and their use are described in detail in the January 2005 issue of Molecules, Volume 10, pages 1-180, which is incorporated herein by reference in its entirety.
A sustained release matrix, as used herein, is a matrix made of materials, usually polymers which are degradable by enzymatic or acid/base hydrolysis or by dissolution. Once inserted into the body, the
matrix is acted upon by enzymes and body fluids. The sustained release matrix desirably is chosen by biocompatible materials including, but not limited to, liposomes, polylactides (polylactide acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyatnino acids, amino acids such phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. The dosage of the composition will depend on the condition being treated, the particular composition used, and other clinical factors such as weight and condition of the patient, and the route of administration.
Further, the term "effective amount" refers to the amount of the composition which, when administered to a human or animal, inhibits proteinase activated receptor activity, particularly undesirable cell proliferation, causing a reduction in cancer or inhibition in the spread and proliferation of cancer or reduction of an inflammatory condition. The effective amount is readily determined by one of skill in the art following routine procedures. For example, compositions of the present invention may be administered parenterally or orally in a range of approximately 1.0 μg to 1.0 g per dose, though this range is not intended to be limiting. The actual amount of composition required to elicit an appropriate response will vary for each individual patient depending on the potency of the composition administered and on the response of the individual. Consequently, the specific amount administered to an individual will be determined by routine experimentation and based upon the training and experience of one skilled in the art.
The composition may be administered in combination with other compositions and procedures for the treatment of diseases. For example, unwanted cell proliferation may be treated conventionally with surgery,
radiation or approved anti-cancer or anti-itiflammatory agents in combination with the administration of the composition, and additional doses of the composition may be subsequently administered to the patient to stabilize and inhibit the growth of any residual unwanted cell proliferation.
Diseases and Conditions To Be Treated
The methods and compositions described herein are useful for treating human and animal diseases and processes mediated by abnormal or undesirable cellular proliferation, particularly abnormal or undesirable endothelial cell proliferation, including, but not limited to, hemangioma, solid tumors, leukemia, tumor metastasis, telangiectasia, psoriasis scleroderma, pyogenic granuloma, myocardial angiogenesis, plaque neovascularization, coronary collaterals, atherosclerosis, ischemic limb angiogenesis, corneal diseases, rubeosis, neovascular glaucoma, diabetic retinopathy, retrolental fibroplasia, arthritis, diabetic neovascularization, macular degeneration, wound healing, peptic ulcer, fractures, keloids, vasculogenesis, hematopoiesis, endometriosis, ovulation, menstruation, and placentation. The methods and compositions are particularly useful for treating angiogenesis-related disorders and diseases by inhibiting angiogenesis and inflammation.
The methods and compositions described herein are particularly useful for treating cancer, arthritis, macular degeneration, and diabetic retinopathy. Administration of the compositions to a human or animal having prevascularized metastasized tumors is useful for preventing the growth or expansion of such tumors and metastases.
The methods and compositions of this invention are useful for treating the following diseases and .. conditions and the symptoms associated with the following diseases and conditions: abnormal growth by endothelial cells, acne rosacea, ' acoustic neuroma, adhesions, angiofibroma, arteriovenous malformations, artery occlusion, arthritis,
asthma, capillary proliferation within plaques, atherosclerotic plaques, atopic keratitis, bacterial ulcers, bartonelosis, benign tumors (such as hemangiomas, acoustic neuromas, neurofibromas, trachomas, pyogenic granulomas), benign, premalignant and malignant vulvar lesions, Best's disease, bladder cancers, block implantation of a blastula, block menstruation (induce amenorrhea), block ovulation, blood-borne tumors (including leukemias, and neoplastic diseases of the bone marrow), bone marrow abnormalities including any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs including multiple myeloma, bone growth and repair, breast cancer, burns, hypertrophy following cancer (including solid tumors: rhabdomyosarcomas, retinoblastoma, Ewing's sarcoma, neuroblastoma, osteosarcoma, blood-borne tumors, leukemias, neoplastic diseases of the bone marrow, multiple myeloma diseases and hemangiomas), carotid obstructive disease, central nervous system malignancy, certain immune reactions (for example immune disorders/reactions), cervical cancers, chemical burns, cholesteatoma especially of the middle ear, choroidal neovascularization, choroiditis, chronic or acute inflammation, chronically exercised muscle, cirrhotic liver, contact lens overwear, corneal diseases, corneal graft neovasularization, corneal graft rejection, corneal neovascularization diseases (including, but not limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, and pterygium keratitis sicca), corpus luteum formation, Crohn's disease, delayed wound healing, diabetes, diabetic (proliferative) retinopathy, diseases caused by the abnormal proliferation of flbrovascular or fibrous tissue including all forms of prolific vitreoretinopathy (PVR), Eales disease, empyema of the thorax, endometriosis, endometrium, epidemic keratoconjuctivitis, excessive or abnormal stimulation of endothelial cells (such as atherosclerosis), eye-related diseases (including rubeosis (neovascularization of the angle), female reproductive system
conditions (including neovascularization of ovarian follicles, corpus luteum, maternal decidua, repair of endometrial vessels, angiogenesis in embryonic implantation sites (ovarian hyperstimulation syndromes), embryonic development, folliculogenesis, luteogenesis, normal menstruating endometrium), fibrinolysis, fibroplasias (retrolental and excessive repair in wound healing), fibrosing alveolitis, fungal ulcers, gastrointestinal infections, peptic ulcer, ulcerative colitis, inflamed polyps, intestinal graft-vs-host reaction, neoplastic tumors, mastocytosis, intestinal ischemia, neovascular glaucoma, gout or gouty arthritis, graft versus host rejection (also chronic and acute rejection), granulation tissue of healing wounds, burn granulations, haemangiomatoses (systemic forms of hemangiomas), hand foot and mouth disease, hair growth, hemangioma, hemophiliac joints, hereditary diseases (including Osler-Weber-Rendu disease), Herpes simplex, Herpes zoster, HHT (hereditary hemorrhagic telangiectasia), hypertrophic scars, hypertrophy following surgery, burns and injury, hyperviscosity syndromes, immune disorders, immune reactions, implantation of embryo (2-8 weeks), infections causing retinitis, infectious diseases caused by microorganisms, inflammation, inflammatory disorders, immune and non-immune inflammatory reactions, inflamed joints, Kaposi's sarcoma, leprosy, leukemias, lipid degeneration
(lipid keratopathy), lipoma, lung cancer, lupus (lupus erythematosis, systemic lupus erythematosis), Lyme disease, age-related macular degeneration (subretinal neovascularization), marginal keratolysis, melanoma, meningiomas, mesothelioma, metastasis of tumors, Mooren's ulcer, mycobacteria diseases, myeloma, multiple myeloma diseases, myopia, neoplasias, neoplastic diseases of the bone marrow (any of various acute or chronic diseases in which unrestrained proliferation of white blood cells occurs which are blood-borne tumors, including leukemias), neovascular glaucoma, neovascularization of the angle, neuroblastoma, neurofibroma, neurofibromatosis, neurofibrosarcoma, nonunion fractures, ocular angiogenic diseases (including diabetic retinopathy,
retinopathy of prematurity, and retrolental fibroplasia, macular degeneration, corneal graft rejection, neovascular glaucoma, and Osier Weber syndrome (Osler-Weber-Rendu disease), ocular histoplasmosis, ocular neovascular disease, ocular tumors, optic pits, oral cancers, osteoarthritis, osteomyelitis, osteosarcoma, Paget's disease (osteitis deformans), parasitic diseases, pars planitis, pemphigoid, phlyctenulosis, polyarteritis, post-laser complications, proliferation of white blood cells (such as any of various acute or chronic neoplastic diseases of the bone marrow, in which unrestrained proliferation of white blood cells occurs), prostate cancer, protozoan infections, pseudoxanthoma elasticum, psoriasis, pterygium (keratitis sicca), pulmonary fibrosis, pyogenic granuloma, radial keratotomy, chronic and acute rejection, retinal detachment, retinitis, retinoblastoma, retinopathy of prematurity, retrolental fibroplasia, rhabdomyosarcomas, rheumatoid arthritis, rheumatoid synovial hypertrophy (arthritis), rosacea (acne rosacea), rubeosis, sarcoidosis, scleritis, scleroderma, sicca (including pterygium (keratitis sicca) and Sjogren's (sicca) syndrome), sickle cell anemia, skin disease (including melanoma, pyogenic granulomas, psoriasis, hemangioma, skin warts, and HPV type 2 (human papillomavirus)), solid tumors (including rhabdomyosarcomas, retinoblastoma, neuroblastoma, osteosarcoma), Stargard's disease, Stevens-Johnson's disease, superior limbic keratitis (superior limbic keratoconjuctivitis, SLK), hypertrophic scars, wound granulation and vascular adhesions, syphilis, systemic lupus, systemic lupus erythematosis, Terrien's marginal degeneration, toxoplasmosis, trachoma, trauma, tuberculosis, ulcerative colitis, ulcers
(including fungal, Mooren's, peptic and bacterial), undesired angiogenesis in normal processes (including wound healing, female reproductive functions, bone repair, hair growth, chronic uveitis, and vascular malfunction), vascular tumors, vein occlusion, vitamin A deficiency, chronic vitritis, Wegener's sarcoidosis, white blood cells diseases
(including any acute or chronic neoplastic diseases of the bone marrow in
which unrestrained proliferation of white blood cells occurs), wound healing and inappropriate wound healing, delayed wound healing (for instance in angiofibroma, arteriovenous malformations, arthritis, atherosclerotic plaques, corneal graft neovascularization, diabetic retinopathy, hemangioma, hemophilic joints, hypertrophic scars, neovascular glaucoma, non-union fractures, pyogenic granuloma, retrolental fibroplasias, scleroderma, solid tumors, trachoma, corpus luteum formations, chronically exercised muscle, rheumatoid arthritis, solid tumors, and chronic inflammatory diseases, inflamed joints, rheumatoid synovial hypertrophy (arthritis), metastasis, oral cancers, cervical cancers, bladder and breast cancers, melanomas, pyogenic granulomas, haemangiomatoses, Kaposi's sarcoma, adhesions, acute and/or chronic inflammation and inflammatory reactions, and chronic and acute rejection). In addition, the methods and compositions of this invention are also useful for treating the following diseases and the symptoms associated with asthma, bronchogenic carcinoma, sarcoidosis, ankylosing spondylosis, chronic obstructive pulmonary disease, thyroiditis (including subacute, acute and chronic thyroiditis, granulomatous (or DeQuervain's thyroiditis) lymphocytic thyroiditis (Hashimoto's thyroiditis), invasive fibrous (Riedel's) thyroiditis, pyogenic or suppurative thyroiditis), dermatitis (including psoriasis, eczema, dermatitis, seborrheic dermatitis, contact dermatitis, atopic dermatitis;, nummular dermatitis; chronic dermatitis, lichen simplex chxonicus, stasis dermatitis, generalized exfoliative dermatitis and Behcet's Syndrome), adenomatous polyposis coli, Alagille syndrome, appendicitis, Barrett esophagus, biliary atresia, biliary tract diseases, Caroli disease, celiac disease, cholangitis, cholecystitis, cholelithiasis, ulcerative colitis, Crohn's disease, digestive system diseases, duodenal ulcer, dysentery, pseudomembranous enterocolitis, esophageal achalasia, esophageal atresia, esophagitis, fatty liver, gastritis, hypertrophic gastritis, gastroenteritis, gastroesophageal
reflux, gastroparesis, hepatitis, chronic hepatitis, Hirschsprung disease, inflammatory bowel diseases, intestinal neoplasms, intestinal neuronal dysplasia, liver cirrhosis, Meckel diverticulum, pancreatic diseases (including pancreatic insufficiency, pancreatic neoplasms, and pancreatitis), peptic ulcer, Peutz-Jeghers syndrome, proctitis, Whipple disease, Zollinger-Ellison syndrome, multiple sclerosis, neuritis, Alzheimer's disease and other neurological diseases, bronchiolitis obliterans organising pneumonia, bronchiectasis, pulmonary fibrosis, chronic obstructive pulmonary syndrome, systemic sclerosis, pleural inflammation, seronegative spondylarthropatiiies, septic arthritis, prolonged pulmonary eosinophilia, simple pulmonary eosinophilia, Lδffler's syndrome, pulmonary eosinophilia with asthma, polyarteritis nodosa, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, idiopathic hypereosinophilic syndrome, allergic bronchopulmonary aspergillosis, bronchocentric granulomatosis, allergic angiitis and granulomatosis (Churg-Strauss Syndrome), idiopathic pulmonary fibrosis, Langerhan's cell granulomatosis (Eosinophilic Granuloma), chronic bronchitis, emphysema, interstitial pneumonia, cutaneous mastocytoma, urticaria pigmentosa, telangiectasia macularis eruptiva perstans (TMEP), systemic mast cell disease, mast cell leukemia, eosinophilic fasciitis, eosinophilic gastroenteritis, eosinophilia myalgia syndrome, systemic mastocytosis, mastocytosis, reactive mastocytosis, neuritis, vestibular neuritis, optic neuritis, lupus nephritis, nephritis, and Parkinson's diseases.
The compositions and methods are further illustrated by the following non-limiting example, which is not to be construed in any way as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present invention.
Where specified enantiomers are shown or are chemically possible, both the R and S or the D and L enantiomers or the racemates or mixtures of the enantiomers in any ratio are envisioned by this invention.
EXAMPLE 1
The compounds provided in Table 1 (ENMD23-0001-ENMD23- 814) were made according to methods well known to those skilled in the art and as described above in the "Detailed Description.". The compounds were tested for efficacy according to the following assay method. A non- proprietary High Throughput Screening (HTS) system for 384-well based biochemical and functional assay formats incorporating a third dimension FLIPR384 for automated screening was used to assess PAR signaling and inhibition. Several cell lines were tested -for endogenous expression of PAR-2 by stimulating with the humane agonist peptide SLIGKV and measuring the calcium flux response. Several transfected cell lines were validated in an agonist titration and an EC50 between 1 and 2 μM was calculated being in good agreement with literature data.
Compound Screening Primary Screening: Two measurements for each plate were performed: the first after compound addition to test a possible agonistic effect and the second after peptide agonist addition to test the antagonistic effect of the compound. Such a combined test on compound agonists is usually not performed for GPCRs but should be included for PAR-2 which is known to be receptive towards agonists.
The compounds were measured in singlicates at lOuM concentration. As described above, two measurements were performed to test agonists and antagonists. The hit population was picked from the screening set and confirmed in replicates. ' Confirmation Screening: hit confirmation screening was next performed on those compounds which demonstrated statistically
significant inhibition of PAR-2 signaling in primary screening. These compounds were repeated as triplicate samples at a single (lOuM) concentration of compound.
The data provided below in Table 2 is the mean percent inhibition of PAR-2 signaling in response to agonist peptide addition. The selected compounds where inhibition is stated to be "Complete Inhibition" demonstrated >90% inhibition at the concentrations tested. In summary, compounds ENMD23-0001-ENMD23-0341 showed "complete" inhibition, ENMD23-0342-ENMD23-0640 showed 60-90% inhibition, and ENMD23-0641-ENMD23-0814 showed 30-60% inhibition.
TABLE 1
Structure ID PAR2 Inhibition (%)
ENMD23-0001 Complete Inhibition
ENMD23-0002 Complete Inhibition
ENMD23-0003 Complete Inhibition
ENMD23-0004 Complete Inhibition
ENMD23-0021 Complete Inhibition
ENMD23-0022 Complete Inhibition
ENMD23-0023 Complete Inhibition
ENMD23-0024 Complete Inhibition
ENMD23-0035 Complete Inhibition
ENMD23-0036 Complete Inhibition
ENMD23-0037 Complete Inhibition
ENMD23-0038 Complete Inhibition
ENMD23-0039 Complete Inhibition
ENMD23-0040 Complete Inhibition
ENMD23-0041 Complete Inhibition
ENMD23-0042 Complete Inhibition
ENMD23-0043 Complete Inhibition
ENMD23-0044 Complete Inhibition
ENMD23-0050 Complete Inhibition
ENMD23-0051 Complete Inhibition
ENMD23-0052 Complete Inhibition
ENMD23-0053 Complete Inhibition
ENMD23-0054 Complete Inhibition
ENMD23-0065 Complete Inhibition
ENMD23-0066 Complete Inhibition
ENMD23-0067 Complete Inhibition
ENMD23-0068 Complete Inhibition
ENMD23-0069 Complete Inhibition
ENMD23-0095 Complete Inhibition
ENMD23-0096 Complete Inhibition
ENMD23-0097 Complete Inhibition
ENMD23-0098 Complete Inhibition
ENMD23-0099 Complete Inhibition
ENMD23-0145 Complete Inhibition
ENMD23-0146 Complete Inhibition
ENMD23-0147 Complete Inhibition
ENMD23-0148 Complete Inhibition
ENMD23-0149 Complete Inhibition
ENMD23-0156 Complete Inhibition
ENMD23-0157 Complete Inhibition
ENMD23-0158 Complete Inhibition
ENMD23-0159 Complete Inhibition
ENMD23-0170 Complete Inhibition
ENMD23-0171 Complete Inhibition
ENMD23Λ)172 Complete Inhibition
ENMD23-0173 Complete Inhibition
ENMD23-0174 Complete Inhibition
ENMD23-0176 Complete Inhibition
ENMD23-0177 Complete Inhibition
ENMD23-0178 Complete Inhibition
ENMD23-0179 Complete Inhibition
ENMD23-0205 Complete Inhibition
ENMD23-0206 Complete Inhibition
ENMD23-0207 Complete Inhibition
ENMD23-0208 Complete Inhibition
ENMD23-0209 Complete Inhibition
ENMD23-0215 Complete Inhibition
ENMD23-0216 Complete Inhibition
ENMD23-0217 Complete Inhibition
ENMD23-0218 Complete Inhibition
ENMD23-0219 Complete Inhibition
ENMD23-0231 Complete Inhibition
ENMD23-0232 Complete Inhibition
ENMD23-0233 Complete Inhibition
ENMD23-0234 Complete Inhibition
ENMD23-0280 Complete Inhibition
ENMD23-0281 Complete Inhibition
ENMD23-0282 Complete Inhibition
ENMD23-0283 Complete Inhibition
ENMD23-0284 Complete Inhibition
ENMD23-0285 Complete Inhibition
ENMD23-0286 Complete Inhibition
ENMD23-0287 Complete Inhibition
ENMD23-0288 Complete Inhibition
ENMD23-0289 Complete Inhibition
ENMD23-0295 Complete Inhibition
ENMD23-0296 Complete Inhibition
ENMD23-0297 Complete Inhibition
ENMD23-0298 Complete Inhibition
ENMD23-0299 Complete Inhibition
106
Table 2
Claims
1. A method for modifying the activity of proteinase activated receptors comprising the administration of proteinase activated receptor ligands, antagonists, enantiomers, racemates and active fragments thereof, wherein the ligands, antagonists, enantiomers, racemates, active fragments, pharmaceutically acceptable salts and prodrugs thereof, comprise compounds selected from the group consisting of ENMD23-
0001-ENMD23-0814.
2. The method of Claim 1, wherein the proteinase activated receptor comprises PAR-I, PAR-2, PAR-3 and PAR-4.
3. The method of Claim 1, wherein the proteinase activated receptor comprises PAR-2.
4. The method of Claim 1, further comprising a pharmaceutically acceptable excipient, carrier or sustained release matrix.
5. A method for treating a human or animal having undesirable cellular proliferation, cancer or inflammation comprising administering to the human or animal a composition comprising proteinase activated receptor ligands, antagonists, enantiomers, racemates, active fragments pharmaceutically acceptable salts and prodrugs thereof, wherein the ligands, antagonists, enantiomers, racemates and active fragments comprise compounds selected from the group consisting of ENMD23-0001-ENMD23-0814.
6. The method of Claim 5, wherein the proteinase activated receptor comprises PAR-I, PAR-2, PAR-3 and PAR-4.
7. The method of Claim 5, wherein the proteinase activated receptor comprises PAR-2.
8. The method of Claim 5, further comprising a pharmaceutically acceptable excipient, carrier or sustained release matrix.
9. The method of Claim 5, wherein the undesirable cellular proliferation occurs during angiogenesis-related disease.
10. The method of Claim 9, wherein the undesirable cellular proliferation is associated with atherosclerosis, solid tumors; blood-borne tumors, such as leukemias; tumor metastasis; benign tumors, hemangiomas, acoustic neuromas, neurofibromas, trachomas, pyogenic granulomas, vascular malfunctions, abnormal wound healing, inflammatory, immune disorders, Behcet's disease, gout, gouty arthritis, abnormal angiogenesis accompanying rheumatoid arthritis, skin diseases, psoriasis, diabetic retinopathy, ocular angiogenic diseases, retinopathy of prematurity, retrolental fibroplasia, macular degeneration, corneal graft rejection, neovascular glaucoma, liver diseases or Oster Webber Syndrome (Osler-Weber-Rendu disease).
11. The method of Claim 5, wherein the undesirable proliferation is associated with inflammatory conditions or inflammatory responses, comprising acute inflammation, chronic inflammation, rheumatoid arthritis, dermatitis, inflammatory bowel disease, inflammatory bowel syndrome, asthma, sepsis, neurogenic pain, and dermatitis.
12. The method of Claim 5, wherein the composition is administered orally, topically, implanted locally, implanted for systematic release, implanted for sustained release, implanted in a biodegradable particle, subcutaneously, intravenously, intra-arterially, intraocularly, transdermally, or transbuccally.
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| US75336305P | 2005-12-22 | 2005-12-22 | |
| US60/753,363 | 2005-12-22 |
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| WO2007076055A9 WO2007076055A9 (en) | 2007-08-30 |
| WO2007076055A3 WO2007076055A3 (en) | 2008-02-28 |
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| WO2007076055A3 (en) | 2008-02-28 |
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