Development of Highly Selective Aldosterone Synthase Inhibitors.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-05-21 eCollection Date: 2025-06-12 DOI:10.1021/acsmedchemlett.5c00222

Guangyuan Shen, Zimo Yang, Yue Lv, Huisi Liu, Xiaopian Tian, Xiangyu Jia, Yuanfeng Xia, Siqin Wang, Lei Jin, Zhilong Hu, Fanglong Yang

引用次数: 0

Abstract

Recent clinical studies have heralded aldosterone synthase inhibitors (ASIs) as a promising therapeutic option for managing resistant hypertension. The efficacy of these compounds is believed to stem from their ability to mitigate aldosterone production. Consequently, we delved into the potential of aldosterone synthase inhibition as a therapeutic strategy for patients with refractory hypertension. Our focus is on the synthesis and optimization of innovative heterocyclic compounds that exhibit aldosterone synthase inhibitory activity. The CYP11B2 inhibitor we have developed exhibits an encouraging pharmacokinetic (PK) profile, along with a robust pharmacokinetic-pharmacodynamic (PK-PD) relationship. This has enabled us to meticulously evaluate the trends in aldosterone inhibition and assess the compound's efficacy in vivo using nonhuman primate models.

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高选择性醛固酮合成酶抑制剂的研究进展。

最近的临床研究预示着醛固酮合成酶抑制剂（ASIs）作为治疗顽固性高血压的有希望的治疗选择。这些化合物的功效被认为源于它们减缓醛固酮产生的能力。因此，我们深入研究了醛固酮合酶抑制作为难治性高血压患者的治疗策略的潜力。我们的重点是合成和优化具有醛固酮合成酶抑制活性的创新型杂环化合物。我们开发的CYP11B2抑制剂显示出令人鼓舞的药代动力学（PK）特征，以及强大的药代动力学-药效学（PK- pd）关系。这使我们能够仔细评估醛固酮抑制的趋势，并利用非人灵长类动物模型评估该化合物在体内的功效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.