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Liver-targeting compound with thyroid hormone receptor stimulating agent characteristics and pharmaceutical composition of liver targeting compound

A technology of thyroid hormones and receptor agonists, which is applied in the field of targeted drugs and biomedicine, can solve problems such as limited applications, and achieve the effects of enhancing targeting, reducing distribution, and reducing side effects

Active Publication Date: 2020-05-08
KYLONOVA (XIAMEN) BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to these adverse effects of thyroid hormones, its further application in lipid metabolism and NASH treatment is limited

Method used

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  • Liver-targeting compound with thyroid hormone receptor stimulating agent characteristics and pharmaceutical composition of liver targeting compound
  • Liver-targeting compound with thyroid hormone receptor stimulating agent characteristics and pharmaceutical composition of liver targeting compound
  • Liver-targeting compound with thyroid hormone receptor stimulating agent characteristics and pharmaceutical composition of liver targeting compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Embodiment 1: Preparation of compound GBL-0603

[0067] 1. Synthesis of Compound A

[0068] 1.1 Synthesis of Compound A-c1

[0069]

[0070] Add DMF (8mL), cbz-6-aminocaproic acid (24mg), HOBt (21.6mg), dlSANC-c12 (84mg) and DIPEA (53.5mg) successively into the reaction flask, after the addition is complete, stir the reaction at room temperature overnight, TLC Detection, the reaction is qualified, stop the reaction, perform post-processing, add water to quench, static phase separation, the aqueous phase is extracted three times with DCM, 20mL / time, the organic phase is combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated , Purified by column to obtain 72.8 mg of white solid.

[0071] 1.2 Synthesis of compound A

[0072]

[0073] Add compound A-c1 (72.8 mg), 15 mL of methanol, and Pd / C (3.4 mg) into the reaction flask in sequence, and perform vacuum / hydrogen replacement. 2 , stirred at 40°C for 1.0 ...

Embodiment 2

[0097] Example 2: Dosage-effect study on the effect of GBL-0603 on lipid metabolism in db mice

[0098] Experimental animals and feeding:

[0099] Thirty male 7-week-old (BKS-db) genetically obese mouse models were selected. Before the experiment, the mice had to adapt to the environment for one week, and healthy mice were selected as the experimental animals. IVC cages were raised, the feeding density was 5 / cage, and the litter was changed twice a week. Experimental animal room requirements: room temperature 22-24°C, relative humidity 40-70%, automatic lighting, 12h alternating light and dark (turn off the light at 08:00 and turn off the light at 20:00), the standard of the experimental animal room meets the national standard GB14925 of the People's Republic of China -2010.

[0100] Drug preparation method:

[0101] Accurately weigh 210 mg of GBL-0603, dissolve it in 35 mL of solvent, and prepare a 6 mg / mL mother solution. Each dosage group is sequentially diluted with th...

Embodiment 3

[0106] Embodiment 3: Add the pharmacodynamic study of accelerant sodium caprate

[0107] Animal feeding is the same as in Example 2. The grouping and dosing schedule are as follows:

[0108]

[0109] Remarks: Sodium caprate was not added to the prescription of drug A, and 20% and 75% of the weight of the main drug were added to the prescriptions of B and C respectively.

[0110] Test operation:

[0111] For G2 / G3 / G4, calculate the solvent volume according to the weight of the drug, add the solvent, vortex repeatedly, and use it after it is completely dissolved. After the preparation is complete, the administration is completed within one hour.

[0112] Before the start of the experiment, the subjects were weighed and randomly divided into groups according to body weight. Fast for 6 hours after the last administration, euthanize the mice in each group, collect blood from the heart, separate serum, detect triglyceride (TG), total cholesterol (CHO), low-density lipoprotein...

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Abstract

The invention belongs to the field of biomedicines, particularly relates to the field of targeting drugs and more specifically relates to a liver-targeting compound with thyroid hormone receptor stimulating agent characteristics and a pharmaceutical composition of the liver targeting compound. The compound is a compound represented by a formula (1). The compound can be used for treating and / or preventing diseases induced by thyroid hormone regulation disorder and can also be used for effectively reducing lipids in blood plasma and liver cells.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to the field of targeted drugs. More specifically, the invention relates to a liver-targeted compound with thyroid hormone receptor agonist properties and a pharmaceutical composition thereof. Background technique [0002] As a chronic liver disease, nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of lipids, mainly triglycerides (TGs), in hepatocytes. The pathological process of NAFLD includes a series of pathological changes in the liver, from simple triglyceride accumulation in hepatic cells (hepatic steatosis) to inflammatory and hepatic balloon damage, developing into non-alcoholic steatohepatitis (NASH), Eventually leading to liver fibrosis and cirrhosis. The exact mechanism of the transition from steatosis to steatohepatitis is unknown. There is a double-hit hypothesis: the first hit involves the accumulation of TGs in hepatocytes, le...

Claims

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Application Information

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IPC IPC(8): C07H15/04C07H1/00A61K31/7032A61P1/16
CPCC07H15/04C07H1/00A61P1/16C07H15/18A61P3/00A61P5/06A61K31/7034A61K47/12A61K31/7032A61P5/14
Inventor 崔坤元王圣军杜艳春
Owner KYLONOVA (XIAMEN) BIOPHARMA CO LTD
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