基于吲哚的磷酸二酯酶5抑制剂的发现：合成与药理学评价
Discovery of Indole-Based PDE5 Inhibitors: Synthesis and Pharmacological Evaluation.
作者信息
Park Shin-Young, Pham Dang, Shukla Param, Edward Justin, John Reshmi, Li Addison, Hadjiargyrou Michael, Mori Mattia, Zuccarello Elisa, Arancio Ottavio, Fiorito Jole
机构信息
Department of Biological and Chemical Sciences, New York Institute of Technology, Old Westbury, New York 11568, United States.
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy.
出版信息
ACS Med Chem Lett. 2025 May 28;16(6):1058-1065. doi: 10.1021/acsmedchemlett.5c00108. eCollection 2025 Jun 12.
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 , with an IC 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 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.
磷酸二酯酶5（PDE5）抑制剂已被提议作为治疗阿尔茨海默病（AD）以及其他病症如癌症和心血管疾病的新疗法。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型含吲哚的PDE5抑制剂。用酰胺基团取代胺基导致鉴定出一种强效类似物，即化合物 ，其IC50为16.11 nM。分子对接模拟进一步突出了酰胺基团在药物 - 靶点相互作用中的重要性。细胞毒性试验和平行人工膜通透性试验验证了该化合物作为进一步药物开发先导物的潜力。化合物 被证明是安全的且可透过血脑屏障。这些含吲哚的PDE5抑制剂的发现为开发PDE5疗法提供了新的视角。
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