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The use of kauranes compounds in the manufacture of medicament for treatment of cardiac hypertropy and pulmonary hypertension

A technology for pulmonary arterial hypertension and kauran, which is applied in the directions of active ingredients of hydroxyl compounds, drug combinations, drug delivery, etc.

Inactive Publication Date: 2018-07-31
KEY PHARMA BIOMEDICAL INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the efficacy of the kaurane compound-Compound A for the prevention and treatment of cardiac or vascular remodeling, cardiac hypertrophy, and pulmonary hypertension characterized by vascular hyperplasia, vascular muscularization, and collagen deposition has not been reported.
There are also no previous reports on the effects of this class of compounds and steviol (compound A) on cGMP or TGF-β, which are recognized factors associated with cardiac hypertrophy and fibrosis

Method used

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  • The use of kauranes compounds in the manufacture of medicament for treatment of cardiac hypertropy and pulmonary hypertension
  • The use of kauranes compounds in the manufacture of medicament for treatment of cardiac hypertropy and pulmonary hypertension
  • The use of kauranes compounds in the manufacture of medicament for treatment of cardiac hypertropy and pulmonary hypertension

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] This case mainly illustrates the effect of Compound A in reducing TAC-induced cardiac hypertrophy and myocardial dilation.

[0093] Adult Wistar rats were treated with vehicle, compound A and sildenafil after TAC induction for 3 weeks. Heart to body weight ratio (HW / BW) is an index reflecting cardiac hypertrophy. In the 3-week TAC model group, while the heart weight ratio (HW / BW) increased by 34.6% (P<0.001), the cross-sectional area of ​​the heart increased by 81.6% (P<0.001). In the 3-week TAC model group, compound A or sildenafil could significantly improve heart and cardiomyocyte hypertrophy (Table 1). After compound A treatment, the increase of cross-sectional area of ​​cardiomyocytes was reduced to 15.1% (1mg / kg) and 4.1% (2mg / kg), while sildenafil reduced the increase of cross-sectional area of ​​cardiomyocytes to 16.3% (70mg / kg). kg). Compound A was more effective than sildenafil.

[0094] Table 1. Effect of compound A on heart weight and body weight of TAC ...

Embodiment 2

[0097] This case mainly illustrates the role of Compound A in inhibiting myocardial remodeling and fibrosis formation.

[0098] Several important transcription factors affect the dynamics of actin, which is regulated by free G-actin and polymerized F-actin. An important consequence of activation of the cardiac hypertrophy pathway is higher F / G actin content. Myocardial F-actin levels were measured by FITC-labeled phalloidin staining. After 9 weeks, the immunofluorescence images of the TAC group showed a significant increase in the green fluorescence of F-actin, which returned to normal after treatment with compound A (8 mg / kg / d) or sildenafil (70 mg / kg / d) group level. After rats were treated with TAC, the level of F-actin was significantly increased, which led to the dynamic changes of actin. Both compound A and sildenafil can reduce the expression of F-actin and maintain the balance of F / G-actin.

[0099] To determine whether compound A could attenuate TAC-induced myocard...

Embodiment 3

[0101] This case illustrates the effect of Compound A on cGMP production.

[0102] Determination of cGMP

[0103] After being treated with vehicle, compound A and sildenafil, the cGMP level of fibroblasts in neonatal rats was detected by ELISA kit. Cells in stationary phase were treated with different doses of compound A (1M, 10M) or sildenafil (100M) for 3 hours. After treatment, cells were lysed with 0.1N HCl, and cGMP was detected by ELISA method. The results are shown in the table below.

[0104] Table 1. Compound A and sildenafil stimulate the production of cGMP (with the control group as reference, %)

[0105] control group

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Abstract

The invention relates novel pharmaceutical use of kaurane compounds of formula (I) in treating and preventing cardiac hypertrophy and myocardium remodeling. The said compounds also can significantly ameliorate pulmonary hypertension and preventing vascular hypertrophy. The said compounds can also be used to suppress fibrosis and to treat erection dysfunction, neurological degenerations and other related diseases by modulating cGMP or cAMP signal pathway and / or by reducing reactive oxygen species (ROS). Wherein R1: hydrogen, hydroxyl or alkoxy. R2: carboxyl, carboxylate, acyl halides, aldehyde,methyl-hydroxyl, and ester, acylamide, acyl or ether group hydrolysable to carboxyl. R3, R4, R5, R6, R8: independently, oxygen, hydroxyl, methyl-hydroxyl, and ester or alkoxymethyl group hydrolysableto methyl-hydroxyl. R7: methyl, hydroxyl, and ester or alkoxymethyl hydrolysable to methyl-hydroxyl. R9: methylene or oxygen.

Description

Background technique [0001] Cardiac hypertrophy is a compensatory response of the heart to pressure overload (Hilfiker-Klemer et al, JACC. 2006:48(9):A55-A66). As cardiac function deteriorates, the heart eventually enters a stage of decompensation. Under the stimulation of stress, the transition from compensation to decompensation is often accompanied by cardiac remodeling (Konstam et al., JACC Cardiovascularimaging. 2011; 4(1):98-108). Cardiac remodeling is a complex process that includes cardiomyocyte enlargement or death, vascular thinning, fibrosis, inflammation, and progressive cardiac dysfunction (Burchfield et al., Circulation.2013; 128(4)388-400) . An increase in the extracellular matrix and associated collagen network surrounding cardiomyocytes increases cardiac stiffness. Disorder and fibrosis of the interstitial network impairs systolic function and contributes to adverse myocardial remodeling after hypertensive heart disease. Cardiac fibroblasts, the most abund...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/045A61P3/00A61P9/00A61P15/10A61P25/00A61K31/19
CPCA61K31/19A61K9/0019A61K9/08A61K47/10A61P9/00A61P9/12A61K31/045A61P15/10
Inventor 谭文
Owner KEY PHARMA BIOMEDICAL INC
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