ElHady Ahmed K, El-Gamil Dalia S, Abdel-Halim Mohammad, Abadi Ashraf H
School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo 11865, Egypt.
Department of Chemistry, Faculty of Pharmacy, Ahram Canadian University, Cairo 12451, Egypt.
Pharmaceuticals (Basel). 2023 Sep 6;16(9):1266. doi: 10.3390/ph16091266.
Phosphodiesterase 5 (PDE5) inhibitors presented themselves as important players in the nitric oxide/cGMP pathway, thus exerting a profound impact on various physiological and pathological processes. Beyond their well-known efficacy in treating male erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), a plethora of studies have unveiled their significance in the treatment of a myriad of other diseases, including cognitive functions, heart failure, multiple drug resistance in cancer therapy, immune diseases, systemic sclerosis and others. This comprehensive review aims to provide an updated assessment of the crucial role played by PDE5 inhibitors (PDE5-Is) as disease-modifying agents taking their limiting side effects into consideration. From a medicinal chemistry and drug discovery perspective, the published PDE5-Is over the last 10 years and their binding characteristics are systemically discussed, and advancement in properties is exposed. A persistent challenge encountered with these agents lies in their limited isozyme selectivity; considering this obstacle, this review also highlights the breakthrough development of the recently reported PDE5 allosteric inhibitors, which exhibit an unparalleled level of selectivity that was rarely achievable by competitive inhibitors. The implications and potential impact of these novel allosteric inhibitors are meticulously explored. Additionally, the concept of multi-targeted ligands is critically evaluated in relation to PDE5-Is by inspecting the broader spectrum of their molecular interactions and effects. The objective of this review is to provide insight into the design of potent, selective PDE5-Is and an overview of their biological function, limitations, challenges, therapeutic potentials, undergoing clinical trials, future prospects and emerging uses, thus guiding upcoming endeavors in both academia and industry within this domain.
磷酸二酯酶5（PDE5）抑制剂在一氧化氮/cGMP途径中发挥着重要作用，从而对各种生理和病理过程产生深远影响。除了在治疗男性勃起功能障碍（ED）和肺动脉高压（PAH）方面的众所周知的疗效外，大量研究还揭示了它们在治疗多种其他疾病中的重要性，包括认知功能、心力衰竭、癌症治疗中的多药耐药性、免疫疾病、系统性硬化症等。这篇综述旨在对PDE5抑制剂（PDE5-Is）作为疾病改善药物所起的关键作用进行更新评估，同时考虑到它们的局限性副作用。从药物化学和药物发现的角度，系统地讨论了过去10年中已发表的PDE5-Is及其结合特性，并阐述了其性质的进展。这些药物面临的一个持续挑战在于其有限的同工酶选择性；考虑到这一障碍，本综述还强调了最近报道的PDE5变构抑制剂的突破性进展，这些抑制剂表现出前所未有的选择性水平，这是竞争性抑制剂很少能达到的。对这些新型变构抑制剂的意义和潜在影响进行了细致的探讨。此外，通过考察PDE5-Is更广泛的分子相互作用和效应谱，对多靶点配体的概念进行了严格评估。这篇综述的目的是深入了解强效、选择性PDE5-Is的设计，并概述其生物学功能、局限性、挑战、治疗潜力、正在进行的临床试验、未来前景和新用途，从而指导学术界和工业界在该领域的未来努力。
