Synthesis and Evaluation of Diphenylpyrazine Cyclic Amine Derivatives as IP Receptor Agonists

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-21 DOI:10.1021/acsmedchemlett.5c00312

Xianrong Cai*, Guoyi Lin, Juan Tang, Yuhe Wang, Juping Cheng, Guiying Liu, Qiang Wang, Chunru Cheng, Zhenqiang Mu, Pengjun Zhou, Qingquan Fu* and Xiaoli An*,

引用次数: 0

Abstract

Pulmonary arterial hypertension (PAH) is a severe, progressive condition with limited treatments. This study focuses on developing novel IP receptor agonists for PAH therapy. By modifying MRE-269, a highly selective IP receptor agonist, we designed and synthesized 2-cyclic amino-5,6-diphenylpyrazine derivatives. Systematic evaluation revealed that introducing a dimethyl group at the C3 position of the piperidine ring significantly improved antiaggregatory activity. The optimal compound 6c-14S demonstrated a 40-fold increase in potency compared to MRE-269. Docking studies confirmed its high selectivity for the IP receptor, and pharmacokinetic studies showed a 3-fold improvement in half-life, suggesting its potential for therapeutic development.

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二苯基吡嗪环胺衍生物作为IP受体激动剂的合成及评价

肺动脉高压（PAH）是一种严重的进行性疾病，治疗有限。本研究的重点是开发用于多环芳烃治疗的新型IP受体激动剂。通过修饰高选择性IP受体激动剂MRE-269，我们设计并合成了2-环氨基-5,6-二苯吡嗪衍生物。系统评价表明，在哌啶环的C3位置引入二甲基可显著提高抗聚集活性。与MRE-269相比，最佳化合物6c-14S的效力提高了40倍。对接研究证实了其对IP受体的高选择性，药代动力学研究显示半衰期提高了3倍，表明其具有治疗开发的潜力。

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.