Abstract: The emergence of mutations in tyrosine kinases following treatment of cancer patients with molecular-targeted therapy represents a major mechanism of acquired drug resistance. Here, we describe a mutation in the serpentine receptor, Smoothened (SMO), which results in resistance to a Hedgehog (Hh) pathway inhibitor in medulloblastoma. A single amino acid substitution in a conserved glutamic acid residue of SMO maintains Hh signaling, but results in the inability of the Hh pathway inhibitor, GDC-0449, to bind SMO and suppress the pathway. The invention provides screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

Abstract: Disclosed are substituted pyridine compounds as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure wherein E, J, T, the ring system denoted by “B”, T, R3, R4, w and x are as described herein. In certain embodiments, a compound disclosed herein activates the AMPK pathway, and can be used to treat metabolism-related disorders and conditions.

Abstract: This invention comprises the novel compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and X have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

Abstract: The present invention relates to 1-(4-ureidobenzoyl)piperazine derivatives having the general Formula I (We bring to your attention that formula I is not provided on this electronic version as it is provided in the abstract of the paper copy) Wherein R1 is (C1-8)alkyl, (C3-8)cycloalkyl or (C3-8)cycloalkyl(C1-3)alkyl, each of which may be substituted by hydroxy, cyano or halogen; R2 represents 1 or 2 optional halogens; R3 is (C1-6)alkyl, (C3-6)cycloalkyl or (C3-6)cycloalkyl(C1-3)alkyl, each of which may be substituted by one or more halogens; A represents a heteroaryl ring system comprising 1-3 heteroatoms selected from N, O and S, which ring system is 5- or 6-membered when X is C, and 5-membered when X is N; n is 1 or 2; or a pharmaceutically acceptable salt thereof; to pharmaceutical compositions comprising the same, and to the use of a these 1-(4-ureidobenzoyl)piperazine derivatives for the manufacture of a medicament for treating or preventing atherosclerosis and related disorders associated with cholester

Abstract: The present invention relates to compounds of formula (I) wherein R1 and A are as defined in the specification as dual modulators of the serotonin 5-HT2a and dopamine D3 receptors, their manufacture, pharmaceutical compositions containing them and their use as medicaments. Compounds of general formula (I) have high affinity for the dopamine D3 and serotonin (5-Hydroxytryptamine; 5-HT) 5-HT2A receptors and are effective in the treatment of psychotic disorders, as well as other diseases such as depression and anxiety, drug dependence, dementias and memory impairment.

Abstract: The present invention relates to 2-aminocarbonyl-pyridine derivatives of Formula (I) 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.

Abstract: The present invention provides a compound of Formula I or Formula II: enantiomer, diastereomer, prodrug, solvate, metabolite, or pharmaceutically acceptable salt thereof, wherein constituent variables are provided herein. The compounds of Formula I and II are modulators of metalloproteases and are useful in treating diseases associated with metalloprotease activity such as arthritis, cancer, cardiovascular disorders, skin disorders, inflammation and allergic conditions.

Abstract: The present invention is directed to methods of use of a compound of Formula I: and/or a pharmaceutically-acceptable salt, hydrate, solvate, tautomer, optical isomer, or combination thereof, a composition comprising the thiosemicarbazone, a method of administration thereof, and use thereof to treat a cancer.

Abstract: A pharmaceutical preparation including a pharmacologically effective amount of a combination of active ingredients containing an angiotensin II receptor antagonist, a calcium channel blocker and polyvinyl alcohol, wherein the polyvinyl alcohol is in an amount of 5 to 85% by weight of the total weight of the pharmaceutical preparation. A method for the prophylaxis or treatment of hypertension by administering a pharmaceutically effective amount of the pharmaceutical preparation to a patient.

Abstract: The invention relates to a compound of formula wherein R1, R2, X, L, W, n, and o are defined herein and to pharmaceutically suitable acid addition salts thereof, with the exception of the following compounds 6-(4-methyl-piperazin-1-yl)-N-phenethyl-nicotinamide (CAS 199478-31-4), N-(3,4-dichloro-benzyl)-3-fluoro-benzamide (CAS 424815-98-5), N-(4-chloro-benzyl)-3-fluoro-benzamide (CAS 544661-83-8), N-(3-chloro-benzyl)-3-fluoro-benzamide (CAS 796051-07-5), and N-phenethyl-6-phenylamino-nicotinamide (CAS 571913-74-1). The compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1 and are useful for the treatment of CNS disorders.

Abstract: The invention provides protease inhibitors that are chemically modified by covalent attachment of a water-soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from the protease inhibitors not attached to the water-soluble oligomer.

Abstract: The present invention relates to novel compounds of Formula (I), wherein X1, X2, X3, X4, Am and Bn are defined as in Formula (I); invention compounds are modulators of metabotropic glutamate receptors—subtype 4 (“mGluR4”) which are useful for the treatment or prevention of central nervous system disorders as well as other disorders modulated by mGluR4 receptors. The invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR4 is involved.

Abstract: This invention relates to a combination product or medicament comprising at least one novel substituted pyrrole derivative and one or more dyslipidemic agents, antiobesity agents, antihyperglycaemic agents, anti-inflammatory agents or mixture thereof.

Abstract: The present application describes substituted piperidinyl modulators of MIP-1? or CCR-1 or stereoisomers or pharmaceutically acceptable salts thereof. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and transplant rejection using said modulators are disclosed.

Abstract: To provide a novel JAK3 inhibitor that is useful as a preventive and/or therapeutic agent for rejection and graft versus host disease (GvHD) in organ transplantation, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Sjögren syndrome, Behcet's disease, type I diabetes mellitus, autoimmune thyroiditis, idiopathic thrombocytopenic purpura, ulcerative colitis, Crohn's disease, asthma, allergic rhinitis, atopic dermatitis, contact dermatitis, urticaria, eczema, psoriasis, allergic conjunctivitis, uveitis, cancer, leukemia and the like. The pyridine-3-carboxyamide derivative represented by the general formula (1): or its salt or a solvate thereof.

Abstract: [Problem] The present invention provides a 4,6-diaminonicotinamide compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for treating diseases caused by undesirable and/or abnormal cytokine signal transduction. [Means for Solution] The present inventors have extensively studied compounds having a JAK3 inhibitory action, and as a result, they have found that a 4,6-diaminonicotinamide compound which is the compound of the present invention has an excellent JAK3 inhibitory action and is useful as an agent for preventing or treating diseases caused by undesirable and/or abnormal cytokine signal transduction, thereby completing the present invention.

Abstract: The invention provides novel, substituted 3-arylamino pyridine compounds pharmaceutically acceptable salts, solvates and prodrug compounds thereof, wherein W, R1, R2, R9, R10, R11, R12, R13, R14 are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer, restenosis and inflammation. Also disclosed is the use of such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and pharmaceutical compositions containing such compounds.

Abstract: The invention relates to compounds of formula (I): processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of conditions or disorders which are mediated via the GPR38 receptor.

Abstract: The invention relates to a compound of formula wherein R1, R2, X, L, W, n, and o are defined herein and to pharmaceutically suitable acid addition salts thereof, with the exception of the following compounds 6-(4-methyl-piperazin-1-yl)-N-phenethyl-nicotinamide (CAS 199478-31-4), N-(3,4-dichloro-benzyl)-3-fluoro-benzamide (CAS 424815-98-5), N-(4-chloro-benzyl)-3-fluoro-benzamide (CAS 544661-83-8), N-(3-chloro-benzyl)-3-fluoro-benzamide (CAS 796051-07-5), and N-phenethyl-6-phenylamino-nicotinamide (CAS 571913-74-1). The compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1 and are useful for the treatment of CNS disorders.

Abstract: The present invention relates to Azine Derivatives, pharmaceutical compositions comprising the Azine Derivatives and the use of these compounds for treating or preventing allergy, an allergy-induced airway response, congestion, a cardiovascular disease, an inflammatory disease, a gastrointestinal disorder, a neurological disorder, a metabolic disorder, obesity or an obesity-related disorder, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose.

Abstract: The present invention provides compounds of formula (I) in which n, y, X1, X2, A, B, R1, R2, R3, R4 and R5 are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them and their use in therapy.

Abstract: A method of treating esophageal cancer, containing the step of administering to a patient suffering from esophageal cancer, a compound or a salt thereof, wherein the compound is: N-(2-fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N?-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-[4-({2-[(azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N?-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-{2,5-difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N?-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N?-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-{[2-({[methyl(1-methyl-piperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N?-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide, or N-(2,5-difluoro-4-{[2-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N?-(4-fluorophenyl)

Abstract: There is provided a novel carbamoyloxy arylalkanoyl arylpiperazine derivative compound having abundant racemic or enantiomeric characteristics, represented by the Formula 1, and pharmaceutically available salts or hydrates thereof. Also, there are provided a pharmaceutical composition for treating pain, anxiety or depression including an effective amount of the compound, and a method for treating pain, anxiety or depression in mammals by administering an effective amount of the compound to the mammals in need of treatment thereof.

Abstract: The invention relates to substituted pyridines and to processes for preparation thereof, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of haematological disorders, preferably of leukopenia and neutropenia.

Abstract: The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Abstract: Disclosed herein are substituted piperazine late Na+ channel modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

Abstract: The invention relates to a compound of Formula (I) and/or a pharmaceutically-acceptable salt, hydrate, solvate, tautomer, optical isomer, E-isomer, Z-isomer, or combination thereof, wherein X is selected from S or O; R5 is selected from a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or (Formula II) and the remaining substituents are described herein; and a composition comprising the thiosemicarbazone and/or the semicarbazone. The invention also relates to a method of administration of a thiocarbazone and/or a semicarbazone; and use thereof to treat a cancer.

Abstract: The present invention provides a compound of formula I; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Abstract: The present invention relates to novel piperazine derivatives (I); to processes for their preparation; to pharmaceutical compositions containing the derivatives; and to the use of the derivatives in therapy to treat diseases for which blocking the Cav2.2 calcium channels is beneficial.

Abstract: The present invention provides a method for the treatment of schizophrenia which comprises administering a compound of formula wherein the substituents are as described herein or a pharmaceutically active acid-addition salt thereof. In particular, the invention provides methods for treating both positive and negative symptoms of schizophrenia through dual inhibition of NK1 and NK3 receptors. The invention also provides novel compounds with formula I and methods for preparing compounds of the invention.

Abstract: The invention provides novel inhibitors of hedgehog signaling that are useful as a therapeutic agents for treating malignancies where the compounds have the general formula I: wherein A, X, Y R1, R2, R3, R4, m and n are as described herein.

Abstract: To provide a compound usable for treatment of diseases associated with fatty acid amide hydrolase (FAAH), especially for treatment of urinary frequency and urinary incontinence, overactive bladder and/or pain. We have found that a novel pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative and its pharmaceutically acceptable salt has a potent FAAH-inhibitory activity. Further, the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative of the present invention has an excellent effect for increasing an effective bladder capacity, an excellent effect for relieving urinary frequency and an excellent anti-allodynia effect, and is therefore usable for treatment of urinary frequency and urinary incontinence, overactive bladder and/or pain.

Abstract: The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Abstract: The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: or a pharmaceutically acceptable salt, solvate or ester thereof. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example(s) include, psoriasis), autoimmune diseases (non-limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non-limiting example(s) include, allograft rejection, zenograft rejection), infectious diseases (e.g., tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula 1.

Abstract: The invention relates to a method of treatment and/or prevention of brain, spinal or nerve injury comprising administration to a person in need of such treatment, of a therapeutically effective amount of an NK-1 receptor antagonist compound of the formula wherein the meanings of R, R1, R2, R2?, R3, and R4 are explained in the specification and the pharmaceutically acceptable acid addition salts and the prodrugs thereof either alone or in combination with a magnesium salt. Exemplified is the use of N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide. The invention also relates to pharmaceutical composition comprising one or more such NK-1 receptor antagonists, optionally in combination with a magnesium salt, and a pharmaceutically acceptable excipient for the treatment and/or prevention of brain, spinal or nerve injury.

Abstract: The present invention relates to piperazine derivatives that act as inhibitors of stearoyl-CoA desaturase. The invention also relates to methods of preparing the compounds, compositions containing the compounds, and to methods of treatment using the compounds.

Abstract: This invention comprises the novel compounds of formula (I) wherein R1, R2 and X have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

Abstract: The present invention relates to acid addition salts of aripiprazole, a process for preparing said acid addition salts and their use to prepare or purify aripiprazole in the form of a free base or in the form of a pharmaceutically acceptable salt.

Abstract: In its many embodiments, the present invention discloses novel compounds, as inhibitors of HDM2 protein methods for preparing such compounds, pharmaceutical compositions including one or more such compounds, methods of treatment, prevention, inhibition, of one or more diseases associated with the HDM2 protein or P53 using such compounds or pharmaceutical compositions.

Abstract: The present invention relates to methods for treating a subject suffering from tinnitus, hearing loss, or tinnitus and hearing loss comprising administering to the subject an effective amount of an NK1 receptor antagonist alone, or in combination with an effective amount of a selective serotonin reuptake inhibitor. Compositions and pharmaceutical formulations are also provided.

Abstract: Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I): wherein W, V, x, y, R1, R2, R3, R4, R5, R6, R7, R7a, R8, R8a, R9, R9a, R10 and R10a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.

Abstract: This invention is directed to a 3-(amido or sulphamido)-4-(4-substituted-azinyl)benzamide or benzsulphonamide compound as defined herein. The 3-(amido or sulphamido)-(4-substituted-azinyl)benzamide or benzsulphonamide compound is useful as a inhibitor of the chemokine receptor CxCR3, and for preventing or treating a CxCR3 chemokine receptor mediated disease or condition related thereto in a patient in need of such.

Abstract: This invention comprises the novel compounds of formula (I) wherein R1, T, X, Y, A, n, m and p have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

Abstract: Compounds of Formula (I): or pharmaceutically acceptable salts, solvates, or esters thereof, are useful in treating diseases or conditions mediated by CB1 receptors, such as metabolic syndrome and obesity, neuroinflammatory disorders, cognitive disorders and psychosis, addiction (e.g., smoking cessation), gastrointestinal disorders, and cardiovascular conditions.

Abstract: Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I) where x, y, G, J, K, L, M, Q, W, V, R2, R3, R5, R5a, R6, R6a, R7, R7a, R8 and R8a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.

Abstract: Disclosed are compounds of Formula I, wherein the R, R1, R2, R3, X, Y, A, Q, E, and G are defined herein. These compounds bind to aspartic proteases to inhibit their activity and are useful in the treatment or amelioration of diseases associated with aspartic protease activity. Also disclosed are methods of use of the compounds of Formula I for ameliorating or treating aspartic protease related disorders in a subject in need thereof.

Abstract: Provided herein are arylsulfonamides that are useful for modulating CCR3 activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a CCR3-mediated disorder, disease, or condition.

Abstract: A compound represented by the formula (I) or a salt thereof; and an agent for protecting a brain/neuronal cell or a therapeutic agent for sleep disorder comprising the compound or salt: wherein Z represents an oxygen or sulfur; R1 represents an aryl or heterocyclic group which may be substituted, provided that R1 is not a 3-ethyl-6-methoxy-2-methyl-5-naphthalen-1-yl group; R1a represents a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxyl group or the like; R2 represents a piperidin-1,4-diyl or piperazin-1,4-diyl which may be substituted; R3 represents a bivalent group which is formed by removing two hydrogen atoms from a benzene ring or 6-membered aromatic heterocyclic ring which may have a substituent, provided that R3 is not a pyridazin-3,6-diyl; and R4 represents a group which is formed by removing one hydrogen atom from a benzene ring or 5- to 6-membered heterocyclic ring which may be substituted, provided that the substituent on the heterocyclic ring is not a phenylethyl group whic

Abstract: Substituted spiro-amide compounds corresponding to formula I in which R5 through R8, D, X, Y and Z have defined meanings, processes for preparing such spiro-amide compounds, pharmaceutical compositions containing such compounds, and methods of using such spiro-amide compounds for treating and/or inhibiting disorders or disease states mediated at least in part by the bradykinin 1 receptor.

Abstract: The present invention relates to new D3 and D2 dopamine receptor subtype preferring ligands of formula (I): wherein R1 and R2 represent independently a substituent selected from hydrogen, alkyl, aryl, cycloalkyl, aroyl, or R1 and R2 may form a heterocyclic ring with the adjacent nitrogen atom; X represents an oxygen or sulphur atom; n is an integer of from 1 to 2, and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, to the processes for producing the same, to pharmaceutical compositions containing the same and to their use in therapy and/or prevention of a condition which requires modulation of dopamine receptors.