245 results about "Plasma kallikrein inhibitor" patented technology

The present invention is concerned with new compounds, and particularly those having a fused bicyclic ring substituted with an amidine moiety. These compounds are each potent inhibitors of Factor D of the alternate pathway of complement, C1s of the classical pathway of complement, Factors Xa, XIIa, VIIa and thrombin of the coagulation pathway, plasmin in the fibrinolytic pathway, and kallikrein and high molecular weight kininogen in the inflammatory pathways. These proteases, which have serine in their active site, are called serine proteases and they are pivotal to most of the processes of inflammation and coagulation. In fact, these various systems are interactive with one another and it is difficult to activate one pathway without it influencing the others.

The invention relates to the application of kallikrein 11, free PSA, and total PSA in the detection of prostate cancer. These markers may be used for the diagnosis, monitoring, staging, progression, prevention, treatment, and prognosis of prostate cancer, and as indicators before surgery or after relapse. A particular aspect of the invention provides a method for distinguishing prostate cancer from benign prostatic hyperplasia (BPH).

The present invention provides compounds of Formula (I):or a stereoisomer or pharmaceutically acceptable salt or hydrate form thereof, wherein the variables A, B, L1, L2, X1, X2, X3, X4 and W are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and / or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and / or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and / or inflammatory disorders using the same.

This invention provides: novel protein homologous of a Kunitz domain, which are capable of binding kallikrein; polynucleotides that encode such novel proteins; and vectors and transformed host cells containing these polynucleotides.

The present invention provides compounds of Formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R3, and ring B are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and / or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and / or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and / or inflammatory disorders using the same.

This invention provides: novel protein homologous of a Kunitz domain, which are capable of binding kallikrein; polynucleotides that encode such novel proteins; and vectors and transformed host cells containing these polynucleotides.

The present invention provides compounds that inhibit the activity of plasma kallikrein (PK) and methods of preventing and treating the formation of thrombin during or after a PK dependent disease or condition, for example, after fibrinolysis treatment.

The present invention provides compounds of Formula (I):or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, R3 and R11 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and / or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and / or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and / or inflammatory disorders using the same.

Gene expression profiling and hierarchial clustering analysis readily distinguish normal ovarian epithelial cells from primary ovarian serous papillary carcinomas. Laminin, tumor-associated calcium signal transducer 1 and 2 (TROP-1 / Ep-CAM; TROP-2), claudin 3, claudin 4, ladinin 1, S100A2, SERPIN2 (PAI-2), CD24, lipocalin 2, osteopontin, kallikrein 6 (protease M), kallikrein 10, matriptase and stratifin were found among the most highly overexpressed genes in ovarian serous papillary carcinomas, whereas transforming growth factor beta receptor III, platelet-derived growth factor receptor alpha, SEMACAP3, ras homolog gene family, member I (ARHI), thrombospondin 2 and disabled-2 / differentially expressed in ovarian carcinoma 2 (Dab2 / DOC2) were significantly down-regulated. Therapeutic strategy targeting TROP-1 / Ep-CAM by monoclonal chimeric / humanized antibodies may be beneficial in patients harboring chemotherapy-resistant ovarian serous papillary carcinomas. Claudin-3 and claudin-4 being receptors for Clostridium Perfringens enterotoxin, this toxin may be used as a novel therapeutic agent to treat ovarian serous papillary tumors.

A activator for prekallikrein includes isolated, purified, or substantially purified heat shock protein 90, a phosphate ion, and mixtures thereof. The prekallikrein activator is part of an in vitro system for activating prekallikrein in the absence of FXIIa. The system includes the activator, high-molecular weight kininogen, and zinc ions. A method for activating prekallikrein to produce kallikrein in the absence of FXIIa includes mixing prekallikrein with the activator and a composition comprising high molecular weight kininogen and zinc ions. A method for evaluating the activity of a test drug for the production of kallikrein comprises activating prekallikrein and determining the kallikrein produced. The activity (promoting or inhibiting ability) of the tested drug against the production of kallikrein in the absence of FXIIa can be easily measured. The test drug may be an analgesic, anti-allergy, anti-inflammatory drug.

The present invention provides compounds that inhibit the activity of plasma kallikrein (PK) and methods of preventing and treating the formation of thrombin during or after a PK dependent disease or condition, for example, after fibrinolysis treatment.

The present invention relates to a novel pharmaceutical combination for treating thromboembolic and / or inflammatory diseases, wherein the combination has: (a) a first therapeutic agent independently selected from the group consisting of a selective Factor VIIa inhibitor, a selective Factor XIa inhibitor, a combination of the selective Factor VIIa and XIa inhibitors, or pharmaceutically acceptable salt forms thereof; and (b) a second therapeutic agent comprising a selective plasma kallikrein inhibitor or a pharmaceutically acceptable salt form thereof. The instant invention is also directed to a method and composition suitable for treating thromboembolic and / or inflammatory diseases using the novel combinations.

The present invention provides compounds of Formula (I):or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R3, and ring B are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and / or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and / or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and / or inflammatory disorders using the same.

Methods for diagnosing and monitoring ovarian cancer in a subject comprising measuring a plurality of kallikrein polypeptides, and optionally CA125, or nucleic acids encoding the polypeptides in a sample from the subject. The kallikrein polypeptides include kallikrein 5, kallikrein 6, kallikrein 7, kallikrein 8, kallikrein 10 and kallikrein 11.

The present invention provides compounds of Formula (I):or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein the variables A, B, L1, L2, X1, X2, X3, X4, R4, R5, R13, R14, R15 and R16 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and / or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and / or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and / or inflammatory disorders using the same.

The present invention provides compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R1 to R9 are as defined herein.

The invention relates to proteins comprising serine protease inhibiting peptides, such as Kunitz domain peptides (including, but not limited to, fragments and variants thereof) fused to albumin, or fragments or variants thereof. These fusion proteins are herein collectively referred to as “albumin fusion proteins of the invention.” These fusion proteins exhibit extended shelf-life and / or extended or therapeutic activity in solution. The invention encompasses, therapeutic albumin fusion proteins, compositions, pharmaceutical compositions, formulations and kits. The invention also encompasses nucleic acid molecules encoding the albumin fusion proteins of the invention, as well as vectors containing these nucleic acids, host cells transformed with these nucleic acids and vectors, and methods of making the albumin fusion proteins of the invention using these nucleic acids, vectors, and / or host cells. The invention also relates to compositions and methods for inhibiting neutrophil elastase, kallikrein, and plasmin. The invention further relates to compositions and methods for treating cystic fibrosis and cancer.

There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin and / or kallikrein, which compounds include substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing certain diseases or disorders, which diseases or disorders are amenable to treatment or prevention by the inhibition of thrombin and / or kallikrein.

The invention is a constructing method of a genetic modified chlamydomonas reinhardtii to express kallikrein of human tissue. Firstly kallikrein gene sequence suitable for expression of chlamydomonas reinhardtii kernel genome or expression of chloroplast genome or expression of mitochondrial is designed according to kallikrein gene sequence of human tissue and preferred codon table of chlamydomonas reinhardtii, the gene sequence is synthesized by artificial synthesis, kallikrein gene of human tissue containing non-coded sequence is artificially synthesized, then expression vector of chlamydomonas reinhardtii kernel genome or expression vector of chlamydomonas reinhardtii chloroplast genome or expression vetor of chlamydomonas reinhardtii mitochondrial with mention foreign gene is constructed, then transformed into chlamydomonas reinhardtii by genetic transformation, and genetic modified algal strains capable of expressing kallikrein of human tissue is obtained after screening. The invention lays foundation of treating and preventing some diseases such as hypertention, glomerulonephritis with human original kallikrein gene chlamydomonas reinhardtii and products there.

The invention provides novel peptide prodrugs that contain cleavage sites specifically cleaved by human kallikrein 2 (hK2). These prodrugs are useful for substantially inhibiting the non-specific toxicity of a variety of therapeutic drugs. Upon cleavage of the prodrug by hK2, the therapeutic drugs are activated and exert their toxicity. Methods for treating cell proliferative disorders are also featured in the invention.

The present invention provides compounds of formula (I): (I) compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R5, R6, R7, A, B, U, D, E, W, X, Y and Z are as defined herein.

The present invention provides antibody polypeptides with binding specificity for human kallikrein-2 (hK2), wherein the antibody polypeptide comprises (a) a heavy chain variable region comprising the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2 and SEQ ID NO: 3 and / or (b) a light chain variable region comprising the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 5 and SEQ ID NO: 6, and wherein the heavy chain variable region and light chain variable region comprise framework amino acid sequences from one or more human antibodies. The invention further provides use of said antibody polypeptides in the diagnosis and treatment of prostate cancer.

Disclosed are novel dipeptide analogs compounds of Formula (I), (II) or (III):or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof, which are inhibitors of factor XIa and / or plasma kallikrein, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of thrombotic diseases.

Gene expression profiling and hierarchial clustering analysis readily distinguish normal ovarian epithelial cells from primary ovarian serous papillary carcinomas. Laminin, tumor-associated calcium signal transducer 1 and 2 (TROP-1 / Ep-CAM; TROP-2), claudin 3, claudin 4, ladinin 1, S100A2, SERPIN2 (PAI-2), CD24, lipocalin 2, osteopontin, kallikrein 6 (protease M), kallikrein 10, matriptase and stratifin were found among the most highly overexpressed genes in ovarian serous papillary carcinomas, whereas transforming growth factor beta receptor III, platelet-derived growth factor receptor alpha, SEMACAP3, ras homolog gene family, member I (ARHI), thrombospondin 2 and disabled-2 / differentially expressed in ovarian carcinoma 2 (Dab2 / DOC2) were significantly down-regulated. Therapeutic strategy targeting TROP-1 / Ep-CAM by monoclonal chimeric / humanized antibodies may be beneficial in patients harboring chemotherapy-resistant ovarian serous papillary carcinomas.

Compounds having the general formula I are useful for inhibiting serine protease enzymes, such as Tissue Factor VIIa, factor Xa, thrombin and kallikrein and have improved permeability properties. These compounds may be used in methods of preventing and / or treating clotting disorders.

The present invention provides compounds of formula (I): (I) compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R5, R6, R7, A, B, W, X, Y and Z are as defined herein.

The invention relates to a preparation of an ELISA kit of human tissue kallikrein. The technical scheme is achieved as follows: the ELISA kit for testing the content of human tissue kallikrein is characterized in that: (a) the method adopted by the kit is a double antibody sandwich method; (b) a biotin-aviden amplification system is added; (c) the standard substance is pronucleus-expressed and purified human tissue kallikrein; (d) the coated antibody is a polyclonal antibody for resisting the human tissue kallikrein, and a detection antibody is a monoclonal antibody of biotinylation; and (e) the sensitivity is 0.3ng / ml to 500ng / ml. The kit has the characteristics of high sensitivity, strong specificity and favorable repeatability. By adopting the expressed fusion protein as the standard substance, the correlation coefficient of a standard curve is as high as 0.99, and by adopting a batch of human plasma as samples to be tested, both the difference in a group and the difference among groups are lower than 10 percent.

The present invention provides compounds of formula (I), compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R5, R6, R7, R12, R13, A, L, B, n, W, X, Y and Z are as defined herein. ##STR00001##

The present invention provides compounds of Formula (I):or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L1, M and R11 are as defined herein. The compounds of Formula (I) are selective inhibitors of serine protease enzymes of the coagulation cascade and / or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and / or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and / or inflammatory disorders using the same.