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Structure-efficacy Relationship and Pharmacodynamics of Neotype ET_A Receptor Antagonists on Pulmonary Hypertension

Author: PanXueFeng
Tutor: GongZeHui
School: PLA Military Academy of Medical Sciences
Course: Pharmacology
Keywords: ET-1 ET_A receptor antagonist Pulmonary hypertension Structure-Activity Relationship
CLC: R96
Type: Master's thesis
Year: 2007
Downloads: 47
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Abstract

Objective: My Room in the preliminary work on the basis of synthesis of new ET _A receptor antagonist-GF series of compounds structure-activity relationship studies of the prevention and treatment of pulmonary hypertension, developed with independent intellectual property rights. provide experimental evidence for anti pulmonary hypertension drugs. Method: 1. First, examine the the novel ET _A receptor antagonist, physical and chemical properties and its toxicity and skin irritation; 2. Antagonize the vasoconstrictor effect of ET-1 receptor antagonist structure-activity relationship of novel ET _{A preliminary analysis by radioligand receptor binding assay as well as compounds in vitro and the overall level; 3. Comprehensive evaluation on chronic hypoxic pulmonary hypertension rat model, Wistar rats were placed in a low-pressure oxygen chamber within a simulated altitude of 5000 meters altitude hypoxic environment, while slow-release subcutaneous or intravenous saline or test compound, 2 weeks after right heart catheterization detection mean pulmonary arterial pressure of the rats in each group were investigated compounds on rat right ventricular hypertrophy, blood parameters, plasma and lung ET-1 levels and pulmonary vascular morphology. Results: 1. Increase the solubility of the compound after 2, D-Trp is replaced with D-Pro, reduced toxicity, wherein GF004 the LD ₅₀ 1809mg/kg, than the pre-synthesized ETP508 low nearly 6 times; but compound there are still more serious skin irritation; 2. GF series of compounds with ET _A receptor affinity below ETP508 positive drug BQ485; eight compounds role the strength and ETP508 and the positive control drug BQ485 considerable in vitro and overall model slightly stronger; 3. ETP508 prophylaxis (10,20,40 mg / kg, subcutaneous injection) in a dose-dependent reduction in hypoxic pulmonary pressure, percentage inhibition of more than 30%, and can be part of the prevention of right ventricular hypertrophy and pulmonary vascular wall thickening process, hypoxic rat blood indicators improved, while the GF004 can not effectively reduce the hypoxic pulmonary pressure, prevention of right ventricular hypertrophy and thickening of the vessel wall; GF009 and GF063 able to prevent the occurrence of hypoxic pulmonary hypertension and improve blood indicators but has no effect on hypoxic rat right ventricular hypertrophy. Conclusion: By introducing hydrophilic R groups or changing two or three amino acids after synthesis of the new the ET _A receptor antagonist, the solubility increases, reduced toxicity, but a compound in the rat model on the lack of The preventive effect of oxygen-induced pulmonary hypertension also reduced, while the presence of the compound of skin irritation may be associated with the introduction of non-natural amino acids and hydrophilic R groups.}

Structure-efficacy Relationship and Pharmacodynamics of Neotype ET_A Receptor Antagonists on Pulmonary Hypertension

Abstract

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