39 results about "Liver microsomes" patented technology

This invention discloses a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof. Experimental results show that the compound provided by this invention exhibits high inhibitory activity against PAK4 kinase and PAK I / II selectivity, good liver microsomal stability, and rat PK pharmacokinetic properties, especially with low hERG cardiotoxicity risk, representing a significant improvement over prior art compounds.

The present invention provides a compound as a PAK4 inhibitor, having a structure as shown in Formula I or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt. The test results show that the compound prepared by the present invention has high inhibitory activity and selectivity for PAK4 kinase, and its liver microsome stability and rat PK are also improved to a certain extent.

The application belongs to the field of chemical drugs, and discloses a BTK protein degrading agent with a silicon-containing group as a hydrophobic tag, a preparation method, a pharmaceutical composition and application thereof.The structure of the BTK protein degrading agent with the silicon-containing group as the hydrophobic tag is shown in formula I, the linker is a saturated aliphatic chain, an unsaturated aliphatic chain, a connecting structure composed of an aromatic ring and a saturated aliphatic chain, or a connecting structure composed of an aromatic ring and an unsaturated aliphatic chain; and R is a specific silicon-containing group as the hydrophobic tag.A BTK protein degrading agent with a silicon-containing group as a hydrophobic tag is obtained, the preparation process is simple and easy to implement, the obtained BTK protein degrading agent has high liver microsomal metabolic stability, has considerable oral bioavailability, shows high treatment efficiency in in-vivo experiments, has a certain inhibitory effect on the proliferation of various tumor cells, and is suitable for the development of cancer drugs such as leukemia.

The invention belongs to the field of biological medicine, and particularly relates to application of vernoniamycin or a derivative thereof in preparation of a medicine for treating gastric cancer. The invention finds the new application of the ivernonamycin in treating the gastric cancer, the action effect of the ivernonamycin in human primary gastric cancer organs is obviously reduced by more than 4 times compared with that of cis-platinum, and the ivernonamycin has obvious advantages compared with the common chemotherapeutic drug cis-platinum. Besides, in pharmacokinetic experiments of rats and mice, the ivernoniamycin has high plasma exposure and good oral bioavailability, and is suitable for oral administration. In a whole blood environment, the vernoniamycin is basically not metabolized within 120 minutes, and has very high stability. In various types of liver microsomes, the amount of the turtledoamycin can be maintained to be 80% within 60 min, only the turtledoamycin can be seen, the turtledoamycin has a good inhibiting and killing effect on gastric cancer, the pharmacokinetics is excellent, the stability in organisms is high, and the effect can be continuously achieved through oral administration.

The invention discloses a bicyclic gamma-amino acid esterified derivative and application thereof, the bicyclic gamma-amino acid esterified derivative can be used as a pain treatment drug through verification, can change a metabolic pathway and accelerate metabolism of liver microsome, so that the burden on the kidney is reduced, and therefore, the bicyclic gamma-amino acid esterified derivative as the pain treatment drug is more widely applicable to people.

The present invention provides a glucagon analogue containing β - amino acids or a pharmaceutically acceptable salt thereof and its application. By replacing α - amino acids with corresponding β - amino acids at different amino acid sites, the glucagon analogue of the present invention has a glucagon receptor (GCGR) agonistic potency equivalent to or higher than that of natural glucagon, and at the same time has significantly improved plasma stability and liver microsome stability, and thus has better drug - like properties.

The application belongs to the field of chemical drugs, and discloses a PD-L1 protein degrading agent with a silicon-containing group as a hydrophobic tag, a preparation method, a pharmaceutical composition and application thereof. The structure of the PD-L1 protein degrading agent with the silicon-containing group as the hydrophobic tag is shown in formula I, the linker is a saturated aliphatic chain, an unsaturated aliphatic chain, a connecting structure composed of an aromatic ring and a saturated aliphatic chain, or a connecting structure composed of an aromatic ring and an unsaturated aliphatic chain; and R is a specific silicon-containing group as the hydrophobic tag. The application obtains the PD-L1 protein degrading agent with the silicon-containing group as the hydrophobic tag, the preparation process is simple and easy to implement, the obtained PD-L1 protein degrading agent has high liver microsomal metabolic stability, has considerable oral bioavailability, shows high treatment efficiency in in-vivo experiments, has certain inhibition effect on the proliferation of various tumor cells, and is suitable for the development of cancer drugs such as leukemia.

The invention discloses a THK01 ester prodrug as well as a preparation method and application thereof in preparation of an anti-inflammatory drug, and the preparation method comprises the step of reacting THK01 with acyl chloride, anhydride or carboxylic acid in an organic solvent in the presence of a catalyst to obtain a THK01 esterified derivative. The THK01 esterified derivative disclosed by the invention is simple in synthetic route, high in reaction yield and easy to operate and implement; as a prodrug, the THK01 esterified derivative can effectively adjust the physicochemical properties (such as lipid-water partition coefficient) and transmembrane permeability of the compound, and shows typical ester prodrug characteristics in an in-vitro liver microsome experiment; in-vitro and in-vivo experiments show that the compounds can significantly inhibit NO generation and inflammatory reaction at low concentration, and the activity of the compounds is superior to that of positive control drugs, so that the compounds are expected to be developed into novel drugs for treating various inflammation-related diseases.

The invention belongs to the field of biological manufacturing and tissue engineering, and particularly relates to hydrogel containing liver microsomes and a preparation method of the hydrogel. According to the hydrogel, an in-vitro liver metabolism module with long-term stability and high physiological correlation is constructed by integrating the metabolic function of liver microsomes and a bionic 3D matrix, and the hydrogel is used for drug metabolism evaluation and toxicity dynamic monitoring. Through the synergistic effect of the photosensitive matrix and the temperature response material, efficient loading of liver microsomes and long-acting maintenance of enzyme activity are achieved, the problems that in a traditional static culture system, the metabolic rate is unstable, the enzyme activity is prone to inactivation and the like are solved, and a more reliable in-vitro prediction tool is provided for drug research and development.

This invention belongs to the field of drug metabolism and analytical chemistry, specifically relating to a method for the rapid determination of tigustastat and its active metabolite GD-MET-1 concentrations in a human liver microsome incubation system using liquid chromatography-tandem mass spectrometry (LC-MS / MS). The method first prepares stock solutions of tigustastat, GD-MET-1, and an internal standard, and prepares a series of standard curve solutions, quality control solutions, and precipitant solutions containing the internal standard. Next, the sample with the added precipitant solution undergoes vortexing and centrifugation pretreatment. Finally, chromatographic and mass spectrometric conditions are set, and the analysis is performed by LC-MS / MS. This method has been validated for specificity, accuracy, precision, matrix effects, recovery, residues, and stability, and can be reliably used for metabolic stability studies of tigustastat and GD-MET-1 in a human liver microsome incubation system, GD-MET-1 formation studies, metabolic enzyme identification, enzyme kinetic studies, and drug interaction studies.

The invention discloses a tricyclic compound and application thereof, and belongs to the technical field of medicine synthesis. The invention provides a tricyclic compound as shown in a formula I. The tricyclic compound can be used for broad-spectrum virus resistance, can effectively inhibit the activity of SARS-CoV, MERS-CoV, SARS-CoV-2 and other coronaviruses and block the replication of the viruses in the body of a patient, and particularly has more advantages in the aspects of pharmacokinetic property, human CYP inhibition rate, cytotoxicity, human liver microsome stability and the like. The compound disclosed by the invention can be used as a generic coronavirus resisting drug, and particularly provides a new choice for developing a drug for preventing and treating diseases related to novel coronavirus infection. Formula I

This invention belongs to the field of medicinal chemistry, specifically relating to a dimeric compound with endothelin A (ETA) receptor antagonist activity and its applications. The compound of this invention is rapidly metabolized to atrasentan in human liver microsomes. In rats, after oral administration, it exhibits excellent absorption, high bioavailability, and a long half-life, significantly lowering blood pressure and improving kidney injury. Furthermore, its weak binding to P-GP and its non-substrate nature further enhance its bioavailability. The compound of this invention, or its pharmaceutically acceptable salt, holds promise for use in the preparation of drugs for the treatment and prevention of ETA receptor antagonist-related diseases, such as chronic kidney disease and hypertension.

The invention discloses a PDE4 inhibitor with a pyrano naphthyridinone skeleton as well as a preparation method and application of the PDE4 inhibitor. The PDE4 inhibitor is a pyrano naphthyridinone derivative as shown in a general formula (I), a stereoisomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof. The inhibitor has relatively strong inhibitory activity on PDE4, part of compounds reach the activity level of a low nanomole level and are far stronger than positive control rolipram, and the compound has relatively high liver microsome stability and a remarkable effect of resisting internal pulmonary fibrosis, so that the molecule has the potential of being developed into a novel phosphodiesterase 4 inhibitor drug. # imgabs0 #

The present application relates to the technical field of medicine, in particular to a MK-4 analogue, a preparation method and application thereof. The MK-4 analogue provided by the present application is more stable in liver microsomes and has a longer half-life. In the osteogenic experiment of osteoblasts, the osteogenic ability is stronger, which is of great significance for enhancing the specificity, effectiveness and reducing the side effects of drugs, and thus can be used for preparing drugs for preventing and / or treating osteoporosis. As the MK-4 analogue, it is expected to be used for preparing drugs for treating cardiovascular and cerebrovascular diseases, chronic kidney disease, neurodegenerative diseases, diabetes and cancer, etc.

The invention provides a parasite expelling composition and application thereof in yak breeding, the parasite expelling composition comprises albendazole and myrobalan acid, through the synergistic effect of albendazole and myrobalan acid, on one hand, the myrobalan acid inhibits the activity of liver microsome metabolic enzymes, prolongs the half-life period of albendazole, improves the bioavailability and optimizes the pharmacokinetic process, on the other hand, the myrobalan acid inhibits the activity of liver microsome metabolic enzymes, and on the other hand, the myrobalan acid inhibits the activity of liver microsome metabolic enzymes; on the other hand, the two act on parasite tubulin synthesis and a body surface biofilm structure respectively to form double-target synergistic killing, so that the parasite expelling effect is remarkably improved; chebulinic acid can repair gastrointestinal mucosa, regulate flora balance, enhance appetite and effectively counteract irritant injury of albendazole to gastrointestinal tracts; the parasite expelling rate reaches 95% or above, the average daily gain reaches 369 g / d, and no obvious influence is caused to the blood system and liver and kidney functions of yaks; the composition has the characteristics of simple formula, gastrointestinal protection and convenience in administration, is adaptive to the current breeding situation of high parasite infection rate of yaks in plateau pasturing areas, and has a good industrial application prospect.

The invention belongs to the field of chemical drugs, and discloses a BTK protein degradation agent taking a silicon-containing group as a hydrophobic label, and a preparation method, a pharmaceutical composition and application thereof. The structure of the BTK protein degradation agent with the silicon-containing group as the hydrophobic label is shown in a formula I, and linker is a saturated aliphatic chain, an unsaturated aliphatic chain, a connecting structure composed of an aromatic ring and a saturated aliphatic chain or a connecting structure composed of an aromatic ring and an unsaturated aliphatic chain; r is a specific silicon-containing group as a hydrophobic label. The BTK protein degradation agent with the silicon-containing group as the hydrophobic label is obtained, the preparation process is simple and easy to implement, and the obtained BTK protein degradation agent has high liver microsome metabolism stability and considerable oral bioavailability, shows an efficient treatment effect in an in-vivo experiment, has a certain inhibition effect on proliferation of various tumor cells, and has a good application prospect. The compound is suitable for developing drugs for treating leukemia and other cancers. # imgabs0 #

The invention belongs to the field of chemical medicines, and discloses an EGFR (epidermal growth factor receptor) protein degradation agent taking a silicon-containing group as a hydrophobic label as well as a preparation method, a pharmaceutical composition and application of the EGFR protein degradation agent. The structure of the EGFR protein degradation agent with the silicon-containing group as the hydrophobic label is shown as a formula I, and linker is a saturated aliphatic chain, an unsaturated aliphatic chain, a connecting structure composed of an aromatic ring and a saturated aliphatic chain or a connecting structure composed of an aromatic ring and an unsaturated aliphatic chain; r is a specific silicon-containing group as a hydrophobic label. The EGFR protein degradation agent with the silicon-containing group as the hydrophobic label is obtained, the preparation process is simple and easy to implement, and the obtained EGFR protein degradation agent has high liver microsome metabolism stability and considerable oral bioavailability, shows an efficient treatment effect in an in-vivo experiment, has a certain inhibition effect on proliferation of various tumor cells, and has a good application prospect. The method is suitable for developing medicines for treating lung cancer and the like. # imgabs0 #

The invention provides a benzoheterocycle compound, a pharmaceutical composition containing the benzoheterocycle compound and application of the benzoheterocycle compound, and particularly relates to a compound shown in the following formula I, pharmaceutically acceptable salt, stereoisomer, deuterated compound, solvate, prodrug or metabolite of the benzoheterocycle compound, a pharmaceutical composition containing the benzoheterocycle compound and application of the benzoheterocycle compound. The compound disclosed by the invention is a WRN regulating agent with a novel structure, has strong WRN inhibitory activity and MSI HCT116 cell proliferation inhibitory activity, shows excellent selectivity in anti-proliferation activity evaluation of MSI cells HCT116 and MSS cells SW620, shows relatively good stability in in-vitro human liver microsome, has better druggability, and can be applied to preparation of anti-proliferative drugs of human liver microsome, such as liver microsome anti-proliferative drugs, liver microsome anti-proliferative drugs, liver microsome anti-proliferative drugs, liver microsome anti-proliferative drugs, liver microsome anti-proliferative drugs and liver microsome anti-proliferative drugs. The compound can be used as a WRN regulating agent for preparing medicines for preventing or treating diseases related to WRN.

The invention belongs to the technical field of biology, and particularly relates to a liver microsome compound stability prediction method based on a deep neural network, which comprises the following steps: acquiring liver microsome compound molecule data, and representing each liver microsome compound molecule as a corresponding SMILES character string; character group-to-ID processing is carried out on the liver microsome compound molecule data to obtain matrix vector data; constructing a deep neural network model; training a deep neural network model by adopting matrix vector data, calculating loss and carrying out back propagation to train model parameters; and predicting the stability of the liver microsome compound by adopting the trained deep neural network model. According to the invention, high-precision molecular stability prediction can be carried out.

The application discloses a triazolopyridine bromodomain-containing protein 4 (BRD4) small molecule inhibitor and a preparation method and application thereof, a compound or a pharmaceutically acceptable salt or a racemate thereof, the general formula of which is shown as formula (I). The novel synthetic triazolopyridine compound effectively regulates the occurrence and development process of related diseases by inhibiting the activity of BRD4 protein. In addition to the advantage of inhibiting the activity of BRD4 protein, the compound has good water solubility and liver microsomal stability, which means that it can be better absorbed and distributed in the body, thereby improving the therapeutic effect. The compound also has good drugability, so that it can be better applied to various inflammatory, autoimmune diseases and tumor drugs. The application provides a new choice for the treatment of related diseases and is expected to play an important role in clinical practice.

The invention belongs to the field of chemical drugs, and discloses a PD-L1 protein degradation agent taking a silicon-containing group as a hydrophobic label, and a preparation method, a pharmaceutical composition and application thereof. The structure of the PD-L1 protein degradation agent taking the silicon-containing group as the hydrophobic label is as shown in formula I, and linker is a saturated aliphatic chain, an unsaturated aliphatic chain, a connecting structure consisting of an aromatic ring and a saturated aliphatic chain or a connecting structure consisting of an aromatic ring and an unsaturated aliphatic chain; r is a specific silicon-containing group as a hydrophobic label. The PD-L1 protein degradation agent with the silicon-containing group as the hydrophobic label is obtained, the preparation process is simple and easy to implement, and the obtained PD-L1 protein degradation agent has high liver microsome metabolism stability and considerable oral bioavailability, shows an efficient treatment effect in an in-vivo experiment, has a certain inhibition effect on proliferation of various tumor cells, and has a good application prospect in the fields of liver microsome metabolism, liver microsome metabolism, liver microsome metabolism, liver microsome metabolism, liver microsome metabolism, liver microsome metabolism, liver microsome metabolism, liver microsome metabolism, liver microsome metabolism, liver microsome metabolism and liver microsome metabolism. The compound is suitable for developing drugs for treating leukemia and other cancers. # imgabs0 #

The invention belongs to the field of anti-infection drugs, and discloses a protease inhibitor for treating or preventing virus infection and application thereof. The protease inhibitor is a compound represented by the following formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates and isomers thereof: the compound is a novel protease inhibitor, can inhibit proteins encoded by coronavirus or interfere with the life cycle of the coronavirus, and can also be used as an antiviral agent, such as an anti-inflammatory agent, an anti-inflammatory agent and an anti-inflammatory agent. The 3CL protease inhibitor is used for treating respiratory system diseases, and compared with the prior art, the 3CL protease inhibitor provided by the invention is high in activity, lower in cytotoxicity, high in metabolic stability in liver microsomes, higher in bioavailability, better in drug absorption, distribution, metabolism and excretion properties, free of inhibition on main CYP enzymes and lower in DDI risk.

The application belongs to the field of chemical drugs, and discloses a protein degrading agent taking noradamantane as a hydrophobic group, a preparation method, a pharmaceutical composition and application thereof. The application provides a protein degrading agent capable of degrading AR, which is based on noradamantane with a hydrophobic tag function as a hydrophobic group and an enzalutamide parent core as a target protein ligand. The protein degrading agent prepared by the application can effectively induce degradation of AR and AR-V7 in a cancer cell line. Compared with the AR protein degrading agent based on adamantane as a hydrophobic tag reported by the previous person, the protein degrading agent has considerable improvement in liver microsomal metabolic stability, can exhibit excellent in-vivo anti-prostate cancer effect in low-frequency drug administration, can be applied to preparation of an AR degrading agent, can form a pharmaceutical composition, and is suitable for development of a cancer drug such as a prostate cancer drug.

The present invention belongs to the technical field of medicinal chemistry, and specifically relates to a 3,8-disubstituted adenine derivative, a preparation method therefor and the use thereof. The 3,8-disubstituted adenine derivative provided in the present invention has a good inhibitory effect on phosphodiesterase type 8, has a good liver microsomal stability and drug-like properties, can be used in the preparation of a drug for treating and / or preventing diseases associated with phosphodiesterase type 8, and has a good development potential, thereby increasing the available options of drugs for treating diseases associated with phosphodiesterase type 8.

The invention relates to the field of in-vitro drug metabolism evaluation, and particularly discloses a liver microsome-containing liver cell 3D culture model and a construction method thereof. According to the invention, primary hepatocytes are used as a cell biological material, and a three-dimensional hepatocyte model is prepared through a three-dimensional bio-printer in combination with Matrigen glue, rat tail glue and calcium ions; the liver microsome hydrogel containing metabolic enzyme is combined in the middle of the system, and the liver microsome-containing liver cell 3D culture model is jointly formed and used for evaluating drug metabolism and drug interaction in vitro, revealing the treatment effect of liver tissue in the liver on drugs and predicting reasonable application of the drugs. The model is simple in structure and relatively mature in preparation process, is expected to be further applied industrially, and has relatively high popularization value.

Provided are compounds for treating or preventing respiratory syncytial virus diseases. Provided are compounds represented by the following formulas (I-1) and (I-2), and pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotope forms thereof. The compounds have antiviral activity and can be used in the preparation of a drug for treating or preventing viral infection in a subject susceptible to viral infection or experiencing viral infection; compared with ziresovir, the compounds have an equivalent or better inhibitory effect on RSV at the in-vitro cell level and better liver microsome metabolic stability; and the compounds are suitable for administration by inhalation.

The invention discloses a macrocyclic compound as well as an intermediate, a preparation method and application thereof. Specifically provided is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound provided by the invention has one or more of the following effects and advantages: (1) the compound has good inhibitory activity on KRAS G12C mutation; (2) the compound has good inhibitory activity on KRAS G12V mutation; (3) the compound has good inhibitory activity on KRAS G12D mutation; (4) the half-life period is long; (5) the oral bioavailability is high; (6) the stability of the liver microsome is good; (7) the target tissue distribution is high; and (8) the pharmaceutical composition has good pharmacokinetic characteristics and druggability.

The present application provides a kind of compound as PAK4 inhibitor, with the structure shown in formula I or its tautomer, meso, racemate, enantiomer, diastereoisomer or its mixture form, pharmaceutically acceptable hydrate, solvate or salt.The test results show that the compound prepared by the present application has high inhibitory activity and selectivity for PAK4 kinase, and its liver microsomal stability and rat PK have also been improved to a certain extent.

The invention discloses a metabolite for identifying a tryptamine new psychoactive substance 4-HO-DET human liver microsome model and application of the metabolite, and relates to the technical field of liver microsomes. The situation that new psychoactive substances (NPS) are abused in a large amount due to uncontrolled conditions in the global range causes serious social, medical and environmental problems. The tryptamine substance 4-HO-DET, as a large class of new psychoactive substances, is rapidly metabolized after being ingested by a human body, and the concentration of an original drug reserved in biological samples such as hair, urine and blood of the human body is extremely low, so that certain difficulty is brought to detection and monitoring of the tryptamine new psychoactive substances. At present, metabolism detection of tryptamine new psychoactive substances is less at home and abroad, and only a small part of tryptamine substances are controlled. Therefore, research on the metabolic process of the tryptamine substances, analysis of the metabolites and metabolic pathways of the tryptamine substances and determination of the metabolic markers of the tryptamine substances play an important role in drug banning work. A human liver microparticle in-vitro model is established for 4-HO-DET, and the metabolic process is simulated.

The invention belongs to the field of anti-infective drugs, discloses a 3CL protease inhibitor for treating or preventing coronavirus infection and application of the 3CL protease inhibitor, and provides a compound as shown in a formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates and isomers thereof. The 3CL protease inhibitor can inhibit protein coded by coronavirus or interfere the life cycle of the coronavirus, can also be used as an antiviral agent for treating respiratory system diseases, and compared with the prior art, the 3CL protease inhibitor provided by the invention is high in activity, lower in cytotoxicity, high in metabolic stability in liver microsome and higher in bioavailability, and can be applied to preparation of medicines for treating respiratory system diseases. The absorption, distribution, metabolism and excretion properties of the medicine are excellent, main CYP enzymes are not inhibited, and the DDI risk is small.