333 results about "Selective inhibition" patented technology

Disclosed are RAS(ON) multi-selective inhibitor compositions and methods of treating RAS protein-related diseases or disorders using an intermittent dosing regimen. RAS(ON) multi-selective inhibitors having tight binding to cyclophilin A (CypA) result in high exposure levels, prolonged tissue retention, and / or slow clearance rates, thereby increasing the risk of inhibition of wild-type RAS in normal tissues. Accordingly, provided herein are methods for the safe and effective dosing of low KD1 RAS(ON) multi-selective inhibitors using an intermittent dosing regimen. Also provided are methods of selecting or identifying such RAS(ON) multi-selective inhibitors suitable for intermittent administration.

The present invention relates to a voltage-gated sodium channel Nav1.8 selective inhibitor and the use thereof in the preparation of a related drug. The drug is used for treating diseases responsive to the inhibition of voltage-gated sodium channel NaV1.8, such as chronic pain, enterodynia, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia. Specifically, the present invention relates to a compound as shown in formula (X), and an isomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

The present provides a method of treating ovarian cancer, breast cancer, gastrointestinal cancer, lung cancer, cancer of the brain or prostate cancer in a subject in need thereof, comprising administering to the subject a first amount of a selective PARP1 inhibitor or a pharmaceutically acceptable salt thereof, and a second amount of an ATR inhibitor or a pharmaceutically acceptable salt thereof. Also disclosed are compositions and kits comprising a PARP inhibitor and ATR inhibitor.

The present invention provides a compound of Formula Iand pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds are selective inhibitors of plasma kallikrein.

The present invention relates to a substituted pyrimidine-fused ring inhibitor, a method for preparing same, and use thereof. Specifically, the compound of the present invention has a structure represented by formula (I). Further disclosed are a method for preparing the compound, and use of the compound as a KRAS mutation inhibitor. The compound has a good selective inhibition effect on KRAS mutation and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects.

The invention relates to a 5, 9-di-tert-butyl naphtho-indolizine phenothiazine compound as well as a preparation method and medical application thereof. The compound is efficiently synthesized through Ullmann coupling and palladium-catalyzed intramolecular arylation reaction. In-vitro anti-tumor activity research shows that the compound has remarkable selective inhibitory activity on various human tumor cell lines, and particularly, the inhibitory effect on non-small cell lung cancer A549 cells (IC50 = 0.21 mu M) is improved by two orders of magnitude compared with that of cis-platinum; iC50 (half maximal inhibitory concentration) of other cell lines are as follows: 1.26 mu M of prostate cancer PC-3 cells, 6.78 mu M of liver cancer HepG2 cells, 7.99 mu M of cervical cancer Hela cells and 25.46 mu M of breast cancer MCF-7 cells. Preliminary toxicity experiments prove that the compound has the characteristic of low cytotoxicity. The compound can be used as a novel high-efficiency low-toxicity anti-tumor lead compound, and provides an important structural basis for the development of anti-cancer drugs.

This disclosure features structurally-stabilized and / or cysteine-reactive peptide inhibitors for selective targeting of BFL-1, or dual targeting of BFL-1 and MCL-1. Also disclosed are methods of using such structurally-stabilized and cysteine-reactive peptides in the treatment of BFL-1- and / or MCL-1-expressing or -dependent cancers or diseases of cellular excess (e.g., autoimmune or inflammatory conditions). Also provided are combination therapies comprising such structurally-stabilized and / or cysteine-reactive peptides and inhibitors of the DNA damage response pathway, such as an ATM kinase inhibitor, ATR kinase inhibitor, CHK1 / 2 inhibitor, or PARP inhibitor; or an inhibitor of MCL-1, or a selective inhibitor of BCL-2, or an inhibitor of BCL-2 / BCL-XL, for the treatment of BFL-1-expressing or -dependent cancers (e.g., AML), BFL-1 and MCL-1-expressing or -dependent cancers, or diseases of cellular excess (e.g., autoimmune or inflammatory conditions).

The present application relates to the technical field of medicine, in particular to the application of gansix triol A in the preparation of a drug for treating gastric cancer and / or non-small cell lung cancer, gansix triol A plays an anti-gastric cancer role by selectively inhibiting the proliferation of gastric cancer MGC-803 cells and inhibiting angiogenesis, the mechanism involves inhibiting the VEGF / VEGFR2 signal pathway and inducing cell apoptosis; the mechanism of gansix triol A in inhibiting the VEGF / VEGFR2 signal pathway is similar to that of bevacizumab; gansix triol A plays an anti-non-small cell lung cancer role by selectively inhibiting the proliferation of non-small cell lung cancer A549 cells, the mechanism involves inhibiting the MAPK / ERK signal pathway and inducing cell apoptosis. The present application finds that the cytotoxic activity of gansix triol A on MGC-803 cells and A549 cells is significantly stronger than that of tanshinone IIA; gansix triol A has an anti-tumor effect of "one drug with double targets, double inhibition" and "high efficiency and low toxicity".

Myotonic Dystrophy type 1 (DM1) is an inherited disease characterized by multi-systemic symptoms, particularly in skeletal muscles (progressive weakness and atrophy, myotonia). The inventors screened 7 500 bioactive compounds for their ability to improve the myogenic fusion and reduce the molecular hallmarks of DM1 skeletal muscle cells. The inventors found that five compounds, all inhibiting HDAC6, a cytoplasmic histone deacetylase, were effective at the micromolar range in normalizing the myogenic fusion, reducing the number of nuclear foci of mutant DMPK mRNA, decreasing the expression level of DMPK mRNA, restoring the splicing of several genes, and increasing the acetylation of SMAD3, a transcription factor involved in muscle development. The effects of HDAC6 inhibitors were observed both in immortalized and hiPSC-derived skeletal muscle cells from DM1 patients, and in different stages of differentiation. Thus, the present invention relates to the use of selective HDAC6 inhibitors for the treatment of DM1.

The invention relates to the technical field of medicines, in particular to fused tricyclic substituted isoxazolidinyl urea derivatives, pharmaceutically acceptable salts, stereoisomers, pharmaceutical compositions and application thereof. The structure of the fused tricyclic substituted isoxazolidinyl urea derivative is as shown in a formula (I). The fused tricyclic substituted isoxazolidinyl urea derivative disclosed by the invention has obvious TrkA kinase and cell inhibition activity and selective inhibition activity.

Provided are a series of 5,6-dihydrothieno[3,4-h]quinazoline compounds as represented by formula (P) and pharmaceutically acceptable salts thereof, and the use of the compounds or pharmaceutically acceptable salts thereof in the preparation of solid tumor drugs, such as solid tumor drugs associated with selective PLK1 inhibitors.

The present application discloses a TYK2 selective inhibitor and its use, specifically relates to a compound of formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or pharmaceutically acceptable salt thereof, and its use for preparing a drug for treating a disease mediated by TYK2.

The present invention relates to pyrazolo[1,5-a][1,3,5]triazine derivatives and pyrazolo[1,5-a]pyrimidine derivatives and / or pharmaceutically acceptable salts thereof, and the use of these derivatives as pharmaceutically active agents, particularly for the prevention and / or treatment of cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases, and infectious diseases. Furthermore, the present invention relates to pharmaceutical compositions comprising at least one of the pyrazolo[1,5-a][1,3,5]triazine derivatives and pyrazolo[1,5-a]pyrimidine derivatives and / or pharmaceutically acceptable salts thereof.

The invention relates to the field of antitumor drugs, in particular to a benzimidazole spleen tyrosine kinase inhibitor as well as a preparation method and application thereof. The inhibitor has a molecular structure as shown in a formula 1, in the formula 1, an R0 group is an R1 group containing an amide group, the R1 group is selected from at least one of the following groups, and an R3 group is selected from at least one of the following groups: H, F, Cl and Br; according to the benzimidazole inhibitor, the structure of the benzimidazole inhibitor can be optimized by introducing the R1 group of acylamino and the R2 group of multiple cyclic structures, so that efficient selective inhibition on spleen tyrosine kinase (Syk) is realized.

Mcl-1 selective inhibitors, Bcl-2 selective inhibitors, and Mcl-1 / Bcl-2 dual inhibitors and methods of using the same for the treatment of disease are disclosed.

The present disclosure is directed to Hsp90 inhibitors having the Formula (I), subformulae thereof, pharmaceutically acceptable salts, stereoisomer, or tautomer thereof, and methods of use thereof.

Described are synthetic compounds having anti-inflammatory properties and optionally analgesic properties. These compounds are derivatives of FDA-approved anti-inflammatory, such as ibuprofen and indomethacin, and can be formed using reactions under microwave irradiation. Generally, the compounds contains a moiety of the parent drug, a triazolyl heterocycle, and a substituted or unsubstituted aryl group. In some forms, the compounds show anti-inflammatory properties and optionally analgesic properties with similar or higher efficiencies compared with their respective parent drugs, with additional advantages including no or reduced adverse effects (e.g., without ulcerogenic liability in the gastric) and / or selective inhibition of COX-2 over COX-1. Pharmaceutical compositions suitable for the delivery of the compounds to a subject in need thereof are disclosed. The pharmaceutical formulation can be administered by oral administration, parenteral administration, inhalation, mucosal administration, or a combination thereof. Methods for preventing or treating an inflammatory disease or disorder in a subject are also disclosed.

This application relates to a series of novel compounds that are selective inhibitors of phosphodiesterase type 9 ("PDE9") for the treatment of chronic heart failure. More specifically, this application relates to pyrazolo[3,4-d]pyrimidinone compounds for use in the treatment and prevention of chronic heart failure.

The present invention relates to crystalline Form A of a compound of Formula (I) and processes for its preparation and uses thereof. The crystalline Form A has superior properties in terms of physico-chemical stability, aqueous solubility, bioavailability and processing suitability.

Provided herein are pharmacological response activation signatures for use in methods and compositions for predicting the response of a subject suffering from cancer to treatment with select inhibitors.

The present invention provides compounds represented by formula (I) and their racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof. These compounds have good FGFR2 / 3 inhibitory activity and can be used to treat or prevent FGFR2 / 3-mediated disorders and diseases, and can be used to manufacture drugs used for the treatment or prevention of such disorders and diseases. [Formula 1] TIFF2026518289000170.tif53170

Disclosed herein are therapeutic uses of myostatin-selective inhibitors, such as myostatin-selective inhibitors, for treating metabolic disorders, such as obesity. Data presented herein support the notion that selectively targeting myostatin without inhibiting Activin A can achieve equivalent or enhanced efficacy when used in conjunction with a GLP-1 receptor agonist in improving body composition, as compared to broadly antagonizing the ActRII pathway in conjunction with a GLP-1 receptor agonist. Administration of a myostatin-selective inhibitor can prolong the effect of semaglutide on fat mass loss. Moreover, administration of a myostatin-selective inhibitor can elicit positive effects on bone in all parameters evaluated, indicating that diet- or inflammation-induced bone atrophy may be prevented by selective inhibition of the myostatin pathway.

Provided herein are pharmaceutical formulations of the AKT1 E17K selective inhibitor 4-((1-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate.

This invention relates to the prevention and / or treatment of protein tyrosine kinase-mediated diseases, particularly phosphatidylinositol 3-kinase (PI3Ks)-mediated diseases. PI3Ks are well known as oncological targets, and several PI3K inhibitors have been developed that inhibit numerous class 1A PI3K isoforms. The development of selective inhibitors of PI3K-α may enable sufficient targeted inhibition while avoiding some of the known toxic drawbacks of pan-PI3K inhibitors. The inventors have discovered that a novel carbamoti-oil-pyrrolidine-carboxamide compound of formula (I) exhibits advantageous PI3K inhibitory activity, particularly with high selectivity for the isoform PI3K-α. In particular, this invention relates to the compound of formula (I), or deuterated or tritiated forms of the compound of formula (I), and pharmaceutically acceptable salts thereof. [Formula 1] The present invention also relates to pharmaceutical compositions containing a compound of formula (I) for use in the treatment and / or prevention of protein tyrosine kinase-mediated diseases, and to a compound of formula (I).

Provided herein are various forms and compositions of N- (5- (5-((1R, 2S) -2-fluorocyclopropyl) -1, 2, 4-oxadiazol-3-yl) -2-methylphenyl) -7- ( (2-hydroxy-2-methylpropoxy) methyl) imidazo [1, 2-a] pyridine-3-carboxamide useful as a selective inhibitor of c-kit kinase and uses of the same in the treatment of c-kit kinase associated diseases.

The present application provides 1H-imidazo[4,5-h]quinazoline compounds of Formula (I). The compounds are broad-spectrum inhibitors with strong activity against FLT3 kinase and are useful in the treatment of cell proliferative disorders.