Discovery of Indole-Based PDE5 Inhibitors: Synthesis and Pharmacological Evaluation.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-05-28 eCollection Date: 2025-06-12 DOI:10.1021/acsmedchemlett.5c00108

Shin-Young Park, Dang Pham, Param Shukla, Justin Edward, Reshmi John, Addison Li, Michael Hadjiargyrou, Mattia Mori, Elisa Zuccarello, Ottavio Arancio, Jole Fiorito

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Abstract

Phosphodiesterase 5 (PDE5) inhibitors have been suggested as new treatments for Alzheimer's disease (AD) and other conditions such as cancer and cardiovascular diseases. Utilizing the widespread presence of the indole moiety in biomolecules and drugs, previously synthesized quinoline and naphthyridine compounds were modified into novel indole-containing PDE5 inhibitors. Replacing the amine with an amide group led to identifying a potent analogue, compound 14a, with an IC₅₀ of 16.11 nM. Molecular docking simulations further highlight the significance of the amide group in drug-target interactions. A cytotoxicity test and a parallel artificial membrane permeability assay validated the compound's potential as a lead for further drug development. Compound 14a was shown to be safe and blood-brain barrier permeable. The discovery of these indole-containing PDE5 inhibitors provides new perspectives for developing PDE5 therapeutics.

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吲哚类PDE5抑制剂的发现：合成和药理评价。

磷酸二酯酶5 （PDE5）抑制剂已被认为是治疗阿尔茨海默病（AD）和其他疾病（如癌症和心血管疾病）的新方法。利用吲哚部分在生物分子和药物中的广泛存在，先前合成的喹啉和萘啶化合物被修饰成新的含吲哚的PDE5抑制剂。用酰胺基取代胺基，鉴定出有效的类似物化合物14a， IC50为16.11 nM。分子对接模拟进一步强调了酰胺基团在药物-靶标相互作用中的重要性。细胞毒性试验和平行人工膜渗透性试验验证了该化合物作为进一步药物开发的先导物的潜力。化合物14a被证明是安全的，并且可以通过血脑屏障。这些含吲哚的PDE5抑制剂的发现为开发PDE5治疗方法提供了新的视角。

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.