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Synthesis and Activity Evaluation of Novel AVP Receptor Antagonists

Author: JieXiaoShuai
Tutor: XuWeiRen
School: Tianjin Medical University
Course: Pharmacology
Keywords: Congestive heart failure hyponatremia arginine vasopressin V2receptorantagonist desloratadine derivatives synthesis biological activity
CLC: R914
Type: Master's thesis
Year: 2013
Downloads: 24
Quote: 0
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Abstract


Congestive heart failure (CHF), the serious stage and terminal outcome of most cardiovascular disease, is a serious threaten to human life and health. Hyponatremia is a common complication of CHF, resulting in a poor prognosis and increased mortality in patients with CHF. Arginine vasopressin V2receptor antagonists, which can increase the excretion of free water without significant effect on electrolyte excretion, are ideal drugs for the treatment of hyponatremia and potent positive agents for the treatment of heart failure.At present, V2receptor antagonists that are studied both domestic and abroad are benzazepine derivatives. Such compounds can significantly improve hyponatremia, but the treatment of heart failure is still under study. According to "me-too" drug design concepts, total16novel non-benzazepine compounds with a desloratadine nucleu, which could be classified into two types(A and B), were designed. The synthetic routes of compounds of A and B were designed as well.Two series of16new compounds of A and B were synthesized by the reaction of N-acylation and the reduction of the nitro from the starting material desloratadine. The structures of All target products and intermediates were confirmed by1H-NMR and ESI-HRMS, Other physical and chemical data such as melting point and purity were also determined.The biological activity of these compounds was evaluated by the human AVP receptor expressing cell model and rat diuretic effect model. The experimental results showed that most of the compounds had strong affinities to human AVP receptors and further selective V2receptor antagonistic activities as well as diuretic effects were observed. The final results showed that A6, A7, A11and B2, et al, which had the characteristics of strong diuretic activity and long duration of the effect, were worthy of further research and development.

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