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Application of pyrimidone compounds in preparing medicine

A pyrimidinethione and compound technology, which is applied in the application field of pyrimidine (thio) ketone compounds in pharmaceuticals, can solve the problems of airway material lesions and research limitations, and achieve the effect of rapid action and reversible toxic effects in vivo

Inactive Publication Date: 2009-07-15
NORTHEAST NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, research has been severely limited by the fact that airway material from lung transplantation is severely diseased

Method used

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  • Application of pyrimidone compounds in preparing medicine
  • Application of pyrimidone compounds in preparing medicine
  • Application of pyrimidone compounds in preparing medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] This example describes the establishment of a high-throughput cell-based screening model for small molecule inhibitors of CFTR

[0061] Research Cell Membrane CFTR Cl - The basis of ion channel opening and screening of its inhibitors is to establish a cell model with high sensitivity, strong specificity, stability and reliability, and suitable for high-throughput screening. First, we stably co-transfected Fischer cells with a porcine CFTR expression plasmid (SV40 promoter, zeocin as a selection marker) and a halogen-sensitive fluorescent green protein mutant YFP-H148Q expression plasmid (CMV promoter, G418 as a selection marker). Mouse thyroid (fischer rat thyroid, FRT) epithelial cell line. The clone FRT / pCFTR / YFP-H148Q / I152L with high fluorescence intensity, rapid growth, basic chloride ion permeability and stable and high expression on the plasma membrane was selected. For high-throughput screening, suspend FTR cells in F-12 Coon's culture medium (containing 10% fe...

Embodiment 2

[0063] This example describes the high-throughput cell screening method and results of small molecule inhibitors of CFTR

[0064] 1. Compound

[0065] A library of 100,000 structurally diverse drug-like small molecules (molecular weight range 350-550 Daltons) was purchased from ChemBridge Co. (ChemBridge Co. San Diego). The concentration of the compound is 10 mM DMSO solution, which is dispensed on a 96-well plate. In the initial screening, the above-mentioned small molecule compounds were screened. Secondary screening and dose-effect analysis were performed on the screened positive compounds. Conduct structural analysis on the exact high-affinity positive compounds, and purchase or synthesize their analogs for further testing.

[0066] 2. High-throughput screening system for CFTR inhibitors

[0067] Primary screening was performed on a Beckman high-throughput cell assay screening system. The system mainly consists of an automatic manipulator, a 3-meter-long slideway, a c...

Embodiment 3

[0075] This example describes the method and results of the determination of the properties of CFTR small molecule inhibitors

[0076] 1. Compound

[0077] FSK, IBMX, APG, purchased from Sigma Company (Sigma Chemical Co.St.Louis, Mo.) CFTRinh-1, CFTRinh-5, CFTRinh-7 self-synthesized

[0078] 2. Kinetic analysis of CFTR inhibitors inhibiting CFTR ion transport activity

[0079]The FRT / pCFTR / EYFP-H148Q cells were plated in a 96-well plate (Corning-Costar 3904) with a black-walled transparent bottom at a density of 30,000 cells per well, and the culture components were F-12 Coon's medium (containing 10% fetal calf serum , 2mM glutamine, 500u / mL penicillin streptomycin), in a carbon dioxide incubator (37 ℃, humidity 90%, CO 2 The concentration is 5%, the air concentration is 95%) after 24 hours of culture, a monolayer is formed and then used for later use.

[0080] Take the cell culture plate out of the carbon dioxide incubator, wash the cells three times with phosphate buffere...

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Abstract

The invention relates to the application of pyrimidine (thio) ketone compounds in the preparation of medicines for treating secretory diarrhea and autosomal dominant hereditary polycystic kidney disease. Cystic fibrosis transmembrane conductance regulator is a Cl-channel protein activated by cyclic adenosine monophosphate. During the design of the model, multiple activation pathways of CFTR were considered, and multiple activation pathways were combined to screen During the process, it binds at the Cl-transport channel. The application of pyrimidine (thio) ketone compounds in the preparation of drugs for treating secretory diarrhea and autosomal dominant polycystic kidney disease is screened on the basis of screening a large number of compounds by using the model for screening inhibitors directly combined with CFTR. It can effectively prevent and treat the occurrence of swine diarrhea. Effectively inhibits fluid secretion from epithelial cells lining autosomal dominant polycystic kidney cysts. The inhibitory effect is rapid, and there is no obvious toxic effect.

Description

technical field [0001] The invention relates to the application of pyrimidine (thio) ketone compounds in the preparation of medicines for treating secretory diarrhea and autosomal dominant hereditary polycystic kidney disease. The invention also relates to a method for establishing a cystic fibrosis model in a non-human mammal. technical background [0002] Cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl activated by cyclic adenosine monophosphate (adenosine 3'5'-cyclic monophosphate acid, cAMP) - Channel protein, which is expressed in epithelial cells of mammalian airway, small intestine, kidney, pancreas and testis. Hormones (such as β-adrenaline) or toxins (such as cholera toxin) activate cAMP-dependent protein kinases by increasing cAMP levels in the body, thereby causing phosphorylation of CFTR, thereby making CFTR Cl - The passage is open. CFTR is abundantly expressed on epithelial cells, it is Cl - The apical membrane across the epithelium provi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/505A61K9/00A61K49/00A61P1/12A61P13/12
Inventor 麻彤辉杨红
Owner NORTHEAST NORMAL UNIVERSITY
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