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Carboxylesterase inhibitor with tanshinone skeleton structure and application thereof

A technology of carboxylesterase and skeleton structure, which is applied in the field of medicine, can solve the problems of reducing drug dosage and affecting bioavailability, and achieves the effects of high inhibitory activity, high safety, and alleviating diarrhea

Active Publication Date: 2014-09-17
ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In addition, most oral prodrugs containing carboxylate bonds are often metabolized by carboxylesterases distributed in the gastrointestinal tract, and are easily hydrolyzed into water-soluble active drugs before being absorbed into the blood, thereby reducing their absorption and absorption. The amount of drug in the blood, which affects the bioavailability

Method used

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  • Carboxylesterase inhibitor with tanshinone skeleton structure and application thereof
  • Carboxylesterase inhibitor with tanshinone skeleton structure and application thereof
  • Carboxylesterase inhibitor with tanshinone skeleton structure and application thereof

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Embodiment 1

[0027] Embodiment 1. The inhibitory activity determination of tanshinone series compound to carboxylesterase

[0028] Using the hydrolytic metabolism of methyl p-nitrobenzoate and fluorescein diacetate as probe reactions, the IC of a series of tanshinone compounds on carboxylesterase inhibition was determined by means of the in vitro incubation system of human liver microsomes 50 , the specific experimental procedure is as follows:

[0029] (1) In 100 microliters of in vitro metabolic reaction system, containing phosphate buffer at pH 7.4, the concentration of human liver microsomal protein is 10 μg / ml, and the final concentration of inhibitors is in the range of 0.01 μM-25 μM. Incubate for 10 minutes;

[0030] (2) Add the substrate (final concentration: 45 μM) to the reaction system to initiate the reaction; after reacting at 37°C for 30 minutes, add 100 μl of acetonitrile containing the internal standard, shake vigorously, and terminate the reaction;

[0031] (3) Using a h...

Embodiment 2

[0035] Example 2. Cryptotanshinone slows down irinotecan-induced diarrhea in rats

[0036] Eighteen rats were randomly divided into 3 groups: normal control group, irinotecan diarrhea model group and cryptotanshinone + irinotecan diarrhea model group (hereinafter referred to as cryptotanshinone group), with 6 rats in each group. Diarrhea model group followed the Trifan method (Cancer Res 2002;62:5778-84.), injected CPT-11 (Pfizer, 5ml / 0.1g) 150mg / kg / d into the tail vein for 2 consecutive days (d), delayed Sexual diarrhea appeared on d4 and was most severe on d5. Later, the diarrhea gradually improved and disappeared completely on d10. In the cryptotanshinone group, 3 days before the CPT-11 injection, 200 mg / kg, about 1.5 ml per rat, was administered by intragastric administration once a day, and the other two groups were intragastrically administered with equal volume of distilled water. The normal control group was injected with an equal volume of normal saline into the tai...

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Abstract

The invention relates to a strong carboxylesterase inhibitor with a tanshinone structure and application thereof for improving the oral bioavailability of predrug with carboxylic ester structures and weakening diarrhea caused by anti-tumor medicament such as irinotecan. The compound specifically comprises tanshinone I, tanshinone IIA, dihydrotanshinone I, cryptotanshinone and analogues and derivatives thereof. In-vitro activity measurement discovers that the IC50 of the compound for inhibiting carboxylesterase can reach nano mole level; and the compound is high in safety and has a good patent medicament prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a carboxylesterase inhibitor with a tanshinone skeleton structure and an application thereof. Background technique [0002] The tanshinone structural compounds involved in this article have the following two applications: [0003] 1) Reduce the diarrhea caused by antineoplastic drugs such as irinotecan; [0004] 2) Improve the oral bioavailability of prodrugs with carboxylate structure. [0005] Irinotecan (CPT-11) is a prodrug of camptothecin derivative SN38, which is widely used in the treatment of solid tumors such as colorectal cancer (Curr Med Chem2003;10:41-9.). It is activated in vivo by carboxylesterase to SN-38 (Drug Metab Dispos 2004;32:505-11.; Biochem Pharmacol 2011;81:24-31.) to exert anti-tumor activity. However, the drug is accompanied by serious adverse reactions, mainly including: neutropenia and delayed diarrhea (Eur J Cancer 1996; 32A Suppl 3:S1...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/58A61P1/12A61P43/00
Inventor 杨凌刘兆明葛广波邹超宁静洪沫
Owner ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI