Abstract: Disclosed are compounds which inhibit or modulate the activity of protein kinases and pharmaceutical compositions containing such compounds. The disclosed compound contain two or more ligand moieties covalently linked together by one or more linking groups. Such compounds are useful for treating diseases or medical disorders mediated by protein kinases.

Abstract: Compounds of formula (I) 1

Abstract: The present invention has determined that exogenously added glycosylceramide (GlcCer) and other neutral glycolipids such as the homologous Glc-containing globotriaosylceramide (Gb3Cer), dose-dependently prolonged clotting times of normal plasma in the presence but not absence of APC:protein S, indicating GlcCer or Gb3Cer can enhance protein C pathway anticoagulant activity. In studies using purified proteins, inactivation of factor Va by APC:protein S was enhanced by GlcCer alone and by GlcCer, globotriaosylceramide, lactosylceramide, and galactosylceramide in multicomponent vesicles containing phosphatidylserine and phosphatidylcholine. Thus, the present invention provides neutral glycolipids such as GlcCer and Gb3Cer, as anticoagulant cofactors that contribute to the antithrombotic activity of the protein C pathway. The present invention has also determined that a deficiency of plasma GlcCer is a risk factor for thrombosis.

Abstract: The present invention has determined that exogenously added glycosylceramide (GlcCer) and other neutral glycolipids such as the homologous Glc-containing globotriaosylceramide (Gb3Cer), dose-dependently prolonged clotting times of normal plasma in the presence but not absence of APC:protein S, indicating GlcCer or Gb3Cer can enhance protein C pathway anticoagulant activity. In studies using purified proteins, inactivation of factor Va by APC:protein S was enhanced by GlcCer alone and by GlcCer, globotriaosylceramide, lactosylceramide, and galactosylceramide in multicomponent vesicles containing phosphatidylserine and phosphatidylcholine. Thus, the present invention provides neutral glycolipids such as GlcCer and Gb3Cer, as anticoagulant cofactors that contribute to the antithrombotic activity of the protein C pathway. The present invention has also determined that a deficiency of plasma GlcCer is a risk factor for thrombosis.

Abstract: Disclosed are compounds which inhibit or modulate the activity of protein kinases and pharmaceutical compositions containing such compounds. The disclosed compound contain two or more ligand moieties covalently linked together by one or more linking groups. Such compounds are useful for treating diseases or medical disorders mediated by protein kinases.

Abstract: Disclosed are multibinding compounds which are muscarinic receptor antagonists. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is, independently of each other, a muscarinic receptor antagonist or an allosteric modulator provided that at least one of said ligand is a muscarinic receptor antagonist. The multibinding compounds of this invention are useful in the treatment and prevention of diseases such as chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.

Abstract: Oncokinase fusion polypeptides associated with hyperproliferative disorders and the polynucleotides encoding for such fusion polypeptides are provided. The fusion polypeptides have a C-terminal tyrosine kinase domain fused to an N-terminal domain that is not normally fused to the C-terminal tyrosine kinase domain and they possess constitutively activated tyrosine kinase activity. Also provided are methods for detecting and identifying the fusion polypeptides and polynucleotides and methods of diagnosing disease conditions associated with the fusion polypeptides and polynucleotides. In addition, screening assays for identifying agents useful for treating disease conditions associated with such fusion polypeptides and polynucleotides are provided. Furthermore, methods of treating disease conditions associated with the presence of the fusion polypeptides are provided.

Abstract: Disclosed are multibinding compounds which are muscarinic receptor antagonists. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is, independently of each other, a muscarinic receptor antagonist or an allosteric modulator provided that at least one of said ligand is a muscarinic receptor antagonist. The multibinding compounds of this invention are useful in the treatment and prevention of diseases such as chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.

Abstract: Novel multi-binding compounds are disclosed that modulate enzymatic processes. The compounds of the invention comprise from 2-10 ligands covalently connected, each of said ligands being capable of binding to an enzyme, enzyme substrate or enzyme cofactor thereby modulating the biological processes/functions thereof.

Abstract: Compounds of formula (I) in which R1, R2, R3 and R4 have the meanings given in the specification, are receptor tyrosine kinase inhibitors useful in the treatment of proliferative disorders, such as cancer.

Abstract: Disclosed are multibinding compounds which include macrolide antibiotics, aminoglycosides, lincosamides, oxazolidinones, streptoramins, tetracycline and/or other compounds which bind to bacterial ribosomal RNA and/or to one or more proteins involved in ribosomal protein synthesis in the bacterium, which are useful in treating bacterial infections. The compounds adversely affect protein expression and have an antibacterial effect. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is macrolide antibiotic, aminoglycoside, lincosamide, oxazolidinone, streptogramin, tetracycline or other compound which binds to bacterial ribosomal RNA and/or one or more proteins involved in ribosomal protein synthesis in the bacterium.

Abstract: Compounds of formula (I) 1

Abstract: The present invention relates to methods of introducing one or more cysteine residues into a polypeptide which permit the stabilization of the polypeptide by formation of at least one bond, preferably a disulfide bond, between different domains of the polypeptide. The invention also relates to polypeptides containing such introduced cysteine residue(s), nucleic acids encoding such polypeptides and pharmaceutical compositions comprising such polypeptides or nucleic acids. The invention also relates to vectors, viral particles and host cells containing such nucleic acids, and methods of using them to produce the polypeptides of the invention. Exemplified polypeptides include plasma proteins, including hepatocyte growth factor activator and plasma hyaluronin binding protein, as well as blood coagulation factors, such as Factor VIII, Factor V, Factor XII and prothrombin.

Abstract: Disclosed are multibinding compounds which are &bgr;2 adrenergic receptor agonists and are useful in the treatment and prevention of respiratory diseases such as asthma and bronchitis. They are also useful in the treatment of nervous system injury and premature labor.

Abstract: Disclosed are multibinding compounds which include macrolide antibiotics, aminoglycosides, lincosamides, oxazolidinones, streptogramins, tetracycline and/or other compounds at which bind to bacterial ribosomal RNA and/or to one or more proteins involved in ribosomal protein synthesis in the bacterium, which are useful in treating bacterial infections. The compounds adversely affect protein expression and have an antibacterial effect. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is macrolide antibiotic, aminoglycoside, lincosamide, oxazolidinone, streptogramin, tetracycline or other compound which binds to bacterial ribosomal RNA and/or one or more proteins involved in ribosomal protein synthesis in the bacterium.

Abstract: Disclosed are novel multi-binding compounds (agents) which bind cellular receptors. The compounds of this invention comprise a plurality of ligands each of which can bind to such cellular receptors thereby modulating the biological processes/functions thereof. Each of the ligands is covalently attached to a linker or linkers which may be the same of different to provide for the multi-binding compound. The linker is selected such that the multi-binding compound so constructed demonstrates increased modulation or disruption of the biological processes/functions of the cell. Also disclosed is a method for identifying such novel multi-binding compounds which bind cellular receptors and a method for generating a mixture of such novel multi-binding compounds.

Abstract: Novel multibinding compounds are disclosed. The compounds of this invention comprise 2-10 ligands covalently connected, each of the ligands being capable of binding to a ligand binding site in a Ca++ channel , thereby modulating the biological activities thereof.

Abstract: Disclosed are novel multibinding compounds (agents) which bind macromolecular structures including cellular, extracellular, and microbial components derived from vectors, viruses, fungi, yeasts, bacteria, and the like. The compounds of this invention comprise a plurality of ligands each of which can bind to such macromolecular structures thereby modulating the biological processes/functions thereof. Each of the ligands is covalently attached to a linker (framework) to provide for the multibinding compound. The linker is selected such that the multibinding compound so constructed demonstrates increased modulation or disruption of the biological processes/functions of cell as compared to the aggregate of the individual units of the ligand.

Abstract: Novel multi-binding compounds (agents) are disclosed which bind cell membrane transporters including ion channels, molecular transporters and ion pumps. The compounds of this invention comprise from 2 to 10 ligands each of which can bind to such cellular transporters to modulate the biological processes/functions thereof. Each of the ligands is covalently attached to a linker (framework) to provide for a multi-binding compound. The linker is selected such that the multi-binding compound exhibits increased modulation of the biological processes/functions of the transporter as compared to the aggregate of the individual ligand units made available for binding to the transporter.

Abstract: Novel antibacterial agents that act as multibinding agents are disclosed. The compounds of the invention comprise from 2-10 ligands covalently connected, each of said ligands being capable of binding to a transglycosylase enzyme substrate thereby modulating the biological processes/functions thereof.