Abstract: The present invention makes available, inter alia, methods and reagents for modulating smoothened-dependent pathway activation. In certain embodiments, the subject methods can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function mutations.

Abstract: The present invention provides heterocyclic linker compounds useful for linking drug moieties to ligands. The compounds also include drug-ligand conjugates comprising a ligand capable of targeting a selected cell population, and a drug connected to the ligand by a heterocyclic linker moiety. The linker moiety comprises a peptide sequence that is a substrate for an intracellular enzyme, for example a cathepsin, that cleaves the peptide at an amide bond. The peptide further contains a self-immolating moiety which connects the drug and the protein peptide sequence. Upon cleavage of the peptide sequence by an intracellular enzyme the self-immolating moiety cleaves itself from the drug moiety such that the drug moiety is in an underivatized and active form.

Abstract: The present invention relates to phosphonated Rifamycins, and methods of making and using such compounds. These compounds are useful as antibiotics for prophylaxis and/or the treatment of bone and joint infections, especially for the prophylaxis and/or treatment of osteomyelitis.

Abstract: The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I wherein R1, R2, R3, R8, and R9 are defined herein. Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I.

Abstract: Compounds of Formula 1, as shown below and defined herein: and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers mediated at least in part by FAK.

Abstract: The present invention provides Formula (1A) XN O R 3 HN R 5 O R 4 R 2 R 1 (1A) 5 compounds that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by the glucokinase enzyme, where X, R 1, R 2, R 3, R 4, and R 5 are as described herein.

Abstract: Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R4 is —(CH2)n—Z—(CH2)mPO(OR7)(OR8), —(CH2)nZ—(CH2)m—PO(OR7)R9, —(CH2)n—Z—(CH2)m—OPO(OR7)R9, —(CH2)nZ—(CH2)m—OPO(R9)(R10), or —(CH2)nZ—(CH2)m—PO(R9)(R10); R5 and R6 are independently selected from H, alkyl and halogen; Y is R7(CH2)s or is absent; and X, n, Z, m, R4, R5, R6, R7, and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

Abstract: Autotaxin (ATX) is a prometastatic enzyme initially isolated from the conditioned media of human melanoma cells that stimulates a myriad of biological activities including angiogenesis and the promotion of cell growth, survival, and differentiation through the production of lysophosphatidic acid (LPA). ATX increases the aggressiveness and invasiveness of transformed cells, and ATX levels directly correlate with tumor stage and grade in several human malignancies. To study the role of ATX in the pathogenesis of malignant melanoma, we developed antibodies and small molecule inhibitors against recombinant human protein. Immunohistochemistry of paraffin embedded human tissue demonstrates that ATX levels are markedly increased in human primary and metastatic melanoma relative to benign nevi. Chemical screens identified several small molecule inhibitors with binding constants ranging from nanomolar to low micromolar.

Abstract: The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.

Abstract: The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.

Abstract: The present invention relates to compounds of formula I wherein R1, R2, R4, R5, Ra, Rb, n, W and Z are as defined in the application, their preparation and their use as P2Y12 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals.

Abstract: The present invention relates to novel classes of compounds of formula I which are caspase and TNF-alpha inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting caspase and TNF-alpha activity and consequently, can be advantageously used as agents against caspase-, interleukin-1-(“IL-1”), apoptosis-, interferon-? inducing factor-(IGIF), interferon-?-(“IFN-?”), or TNF-alpha mediated diseases, including inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, and degenerative diseases. This invention also relates to processes for preparing the compounds of this invention.

Abstract: A novel method has led to the identification of novel mixed ester-amidates of PMPA for retroviral or hepadnaviral therapy, including compounds of structure (5a) having substituent groups as defined herein. Compositions of these novel compounds in pharmaceutically acceptable excipients and their use in therapy and prophylaxis are provided.

Abstract: The present invention relates to therapeutic and/or prophylactic uses of pyridazine compounds and to pharmaceutical compositions containing one or more of these compounds as an active component for treating a disorder characterized by conduction disturbances, electroconvulsions and/or seizures, in particular epilepsy, more particularly pediatric epilepsy. In an aspect of the invention, the pyridnsine compound has the Formula (Ia) or (Ib) wherein R1, R2, R3, R4, R5, R6 and R7 are as defined in the description.

Abstract: An amino or thiol linker building block for the synthesis of amino or thiol functionalized amino acids and generally of the following structure: is provided. Such building block may be introduced in the 5? end position of an amino acid under standard coupling conditions. Such building block allows in-line coupling control, “trityl-on” purification, and solid support functionalization/derivatization. Such building block is a stable, solid compound and can therefore be easily handled. With the building block of the present invention, deprotection may be carried out under standard detritylation conditions.

Abstract: The present invention relates to phosphonate, nucleoside phosphonate or nucleoside phosphate compounds, compositions containing them, processes for obtaining them, and their use in treating a variety of medical disorders, in particular viral infections, cancers and the like.

Abstract: The present invention relates to pyridines or pyrazines that inhibit kinases. In particular the compounds of the invention inhibit members of the class III PTK receptor family such as FMS (CSF-IR), c-KIT, PDGFR?, PDGFR? or FLT3 and KDR, SRC, EphA2, EphA3, EphA8, FLT1, FLT4, HCK, LCK, PTK5 (FRK), SYK, DDR1 and DDR2 and RET. The compounds of the invention are useful in the treatment of kinase associated diseases such as immunological and inflammatory diseases; hyperproliferative diseases including cancer and diseases involving neo-angiogenesis; renal and kidney diseases; bone remodeling diseases; metabolic diseases; and vascular diseases.

Abstract: There is provided a T-type calcium channel blocker that is a compound of formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof: wherein Ar1 is phenyl group, pyridyl group, furyl group or 2,1,3-benzoxadiazol-4-yl group; nitrogen-containing hetero ring moiety is 1,4-dihydropyridine ring or pyridine ring; Z is a group of formula (2) or CO2R2; Ra and Rb are independently of each other C1-6alkyl group, ANR8R9, CH2OANR8R9, or the like; in case where the nitrogen-containing hetero ring moiety is 1,4-dihydropyridine ring, R1 is C1-6alkyl group, ANR8R9, AN(CH2CH2)2NR8, AN(CH2CH2)2O, AOR8 or benzyl group; R3 is hydrogen atom, C1-20alkyl group, ANR8R9, a group of formula or the like.

Abstract: The disclosure relates to a compound of formula (I): wherein R, R1, R2, R3, R4, R5, R6 and Z are as defined in the specification, to compositions containing them, to processes for preparing them, and to their use in the treatment or prevention of conditions capable of being modulated by the inhibition of the activity of protein kinases.

Abstract: The present invention relates to Arylmethylidene heterocycles, compositions comprising an Arylmethylidene heterocycle, and methods useful for treating or preventing pain comprising administering an effective amount of an Arylmethylidene heterocycle. The compounds, compositions, and methods of the invention are also useful for treating or preventing inflammation.

Abstract: The invention is related to phosphorus substituted anti-inflammatory compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

Abstract: The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.

Abstract: The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.

Abstract: The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.

Abstract: The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.

Abstract: The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.

Abstract: The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.

Abstract: Novel molecular transporter compositions and their use for transporting bioactive substances into cells in living animals are disclosed. To afford in vivo delivery, the composition is covalently linked to the bioactive substance and the resultant composite structure is introduced into the subject. The transporter composition includes multiple guanidine moieties on a dendrimeric scaffold having a tri-functional core. The tri-functional core is a phosphorodiamidate or phosphoramide moiety.

Abstract: Provided herein are phosphadiazine polymerase inhibitor, for example, of Formula III, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.

Abstract: The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I wherein R1, R2, R3, R8, and R9 are defined herein. Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I.

Abstract: This invention provides a method for identifying potential therapeutic agents by contacting a target cell with a candidate therapeutic agent which is a selective substrate for an endogenous, intracellular enzyme in the cell which is enhanced in its expression as a result of selection by biologic or chemotherapy. This invention also provides methods and examples of molecules for selectively killing a pathological cell by contacting the cell with a prodrug that is a selective substrate for an endogenous, intracellular enzyme. The prodrug is subsequently converted to a cellular toxin. Further provided by this invention is a method for treating a pathology characterized by pathological, hyperproliferative cells in a subject by administering to the subject a prodrug that is a selective substrate for an endogenous, overexpressed, intracellular enzyme, and converted by the enzyme to a cellular toxin in the hyperproliferative cell.

Abstract: The present invention relates to compounds of formula I which are prodrugs of caspase inhibitors and pharmaceutically acceptable salts thereof. This invention further relates to the release of caspase inhibitors from these compounds through selective bond cleavage. This invention further relates to pharmaceutical compositions comprising these compounds, which are particularly well-suited for treatment of caspase-mediated diseases, including inflammatory and degenerative diseases. This invention further relates to methods for preparing compounds of this invention.

Abstract: The present invention is related to compounds having formula (I) wherein the dashed line indicates a single or double bond or is absent and wherein A1-A9, Q, R1-R11, T, U, V, W1-W3, X1, X2, Y and Z are as defined in the claims and description, pharmaceutical compositions comprising the compounds and the use of the compounds for the manufacture of a medicament for the treatment of diseases involving abnormal cell proliferation, undesired cell proliferation, abnormal mitosis and/or undesired mitosis.

Abstract: The present invention is related to derivatives of Formula (I) and use thereof in particular for the treatment and/or prophylaxis of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, cancer, respiratory diseases and fibrosis, including multiple sclerosis, arthritis, emphysema, chronic obstructive pulmonary disease, liver and pulmonary fibrosis.

Abstract: The present invention relates to compounds of formula I which are prodrugs of caspase inhibitors and pharmaceutically acceptable salts thereof. This invention further relates to the release of caspase inhibitors from these compounds through selective bond cleavage. This invention further relates to pharmaceutical compositions comprising these compounds, which are particularly well-suited for treatment of caspase-mediated diseases, including inflammatory and degenerative diseases. This invention further relates to methods for preparing compounds of this invention.

Abstract: The present invention relates to compositions and methods for treating the epithelial toxicity caused by administering to a human cancer patient an epidermal growth factor receptor (EGFR) inhibitor. The pharmaceutical composition preferably comprises an EGFR inhibitor and a keratinocyte growth factor (KGF) in a pharmaceutically-acceptable carrier. The method of treatment comprises co-administering to the patient a therapeutically effective amount of KGF with the EGFR inhibitor.

Abstract: The invention is related to phosphorus substituted anti-infective compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

Abstract: Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R4 is —(CH2)n-Z-(CH2)m—PO(OR7)(OR8), —(CH2)nZ-(CH2)m—PO(OR7)Rg, —(CH2)n-Z-(CH2)m—OPO(OR7)Rg, —(CH2)nZ—(CH2)m—OPO(R9)(R10), or —(CH2)nZ—(CH2)m—PO(R9)(R10); R5 and R6 are independently selected from H, alkyl and halogen; Y is R7(CH2)s or is absent; and X, n, Z, m, R4, R5, R6, R7, and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

Abstract: The present invention provides a phosphonic acid diester compound represented by General Formula wherein R1, R2, R3 and R4 are the same or different, and represent hydrogen, halogen, lower alkyl or lower alkoxy; R5 is phenyl having on the phenyl ring 1–3 substituents selected from the group consisting of lower alkyl, halogen-substituted lower alkyl, lower alkoxy, halogen-substituted lower alkoxy, phenoxy, benzyloxy, hydroxyl, halogen, nitro, lower alkylthio, di(lower alkyl)amino, lower alkanolyamino, pyrrolidinyl and phenyl, or the like, provided that R5 is not mono(lower alkoxy)pheny; and R6 is lower alkyl; and an ACAT-1 inhibitor containing the compound as an active ingredient.

Abstract: The present invention relates to N-substituted cyclic aza compounds, pharmaceutical compositions comprising such compounds, and methods of their use for effecting neuronal activities.

Abstract: The invention relates to insecticidal mixtures for protecting plants against attack by pests comprising (a) compounds of the formula (I) ?in which W, X, Y, Z, A, B, D and G are each as defined in the disclosure, and (b) specified agonists or antagonists of nicotinic acetylcholine receptors.

Abstract: A NK1 antagonist having the formula (I), wherein Ar1 and Ar2 are optionally substituted phenyl or heteroaryl, X1 is an ether, thio or imino linkage, R4 and R5 are not both H or alkyl, and the remaining variables are as defined in the in the specification, useful for treating a number of disorders, including emesis, depression, anxiety and cough. Pharmaceuticals compositions. Methods of treatment and combinations with other agents are also disclosed.

Abstract: The present invention describes pyridazinone compounds of formula I which are cyclooxygenase (COX) inhibitors, and in particular, are selective inhibitors of cyclooxygenase-2 (COX-2), COX-2 is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important “housekeeping” enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys. The selectivity of these compounds for COX-2 minimizes the unwanted GI and renal side-effects seen with currently markered non-steroidal anti-inflammatory drugs (NSAIDs).

Abstract: The disclosure includes novel polymorphic and pseudopolymorphic crystalline forms of 5-azacytidine, along with methods for preparing said forms, wherein 5-azacytidine is represented by the formula: The disclosure also includes pharmaceutical compositions comprising said forms.

Abstract: The invention provides compounds of the formula wherein the substituents are as defined in the application. The compounds are valuable glycine transport inhibitors.

Abstract: Novel compounds of unstable inhibitors of the serine peptidase dipeptidyl peptidase IV, are used in the treatment of various disorders, especially of metabolic disorders. The compounds can be used in the treatment of impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidoses, diabetes mellitus, diabetic neuropathy and nephropathy.

Abstract: The present invention provides a method for the preparation of 5-azacytidine, wherein 5-azacytidine is represented by the structure: The method involves the silylation of 5-azacytosine, followed by the coupling of silylated 5-azacytosine to a protected ?-D-ribofuranose derivative. The coupling reaction is catalyzed by trimethylsilyl trifluoromethanesulfonate (TMS-Triflate).

Abstract: The present invention describes pyridazinone compounds of formula I which are cyclooxygenase (COX) inhibitors, and in particular, are selective inhibitors of cyclooxygenase-2 (COX-2). COX-2 is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important “housekeeping” enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys. The selectivity of these compounds for COX-2 minimizes the unwanted GI and renal side-effects seen with currently marketed non-steroidal anti-inflammatory drugs (NSAIDs).

Abstract: Methods are provided for treating diseases associated with abnormal activity of kinases. The method comprises: administering a DNA methylation inhibitor to the patient in therapeutically effective amount; and administering a kinase inhibitor to the patient in therapeutically effective amount, such that the in vivo activity of the kinase is reduced relative to that prior to the treatment.

Abstract: The invention relates to pharmaceutical compositions for topical administration comprising a topically acceptable antiviral substance and an antiinflammatory glucocorticoid in a pharmaceutically acceptable carrier. The pharmaceutical composition can be used in the prophylactic and curative treatment of herpesvirus infections in mammals including man. The invention also relates to the use of a combination of a topically acceptable antiviral substance and an antiinflammatory glucocorticoid for the manufacture of a medicament for said prophylactic and curative treatment.