Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Vidya Vihar, Pilani, 333031, (RJ), India.
Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Vidya Vihar, Pilani, 333031, (RJ), India.
Eur J Med Chem. 2024 Dec 15;280:116932. doi: 10.1016/j.ejmech.2024.116932. Epub 2024 Oct 4.
Neprilysin is a cell surface metallo-endopeptidase, commonly identified as neutral endopeptidase (NEP), that plays a crucial role in the cleavage of peptides, for example, natriuretic peptides, angiotensin II, enkephalins, endothelin, bradykinin, substance P, glucagon-like peptide and amyloid beta. In the case of heart failure, a significant upsurge in NEP activity and expression enhances the degradation of natriuretic peptides. Therefore, NEP inhibitors have gained attention in the field of cardiology. NEP has been studied for over 40 years; however, it has recently gained attention with the US FDA approval of a fixed dose combination of sacubitril (NEP inhibitor) and valsartan (AT-1 inhibitor) for chronic heart failure treatment. The present review elucidates the role of neprilysin in cardiorenal disease, its pathophysiology, and how NEP inhibition benefits. It also summarizes the research advances in NEP inhibitors (NEPi) and their structure-activity relationships. Moreover, the review provides insight into NEPi effectiveness - alone or combined with other cardiorenal protective agents. It is expected to help medicinal chemists synthesize and develop novel NEPi.
Neprilysin 是一种细胞表面金属内肽酶，通常被鉴定为中性内肽酶（NEP），在肽的切割中发挥着关键作用，例如利钠肽、血管紧张素 II、脑啡肽、内皮素、缓激肽、P 物质、胰高血糖素样肽和淀粉样β。在心衰中，NEP 活性和表达的显著增加增强了利钠肽的降解。因此，NEP 抑制剂在心脏病学领域引起了关注。NEP 的研究已经超过 40 年；然而，随着美国 FDA 批准 sacubitril（NEP 抑制剂）和缬沙坦（AT-1 抑制剂）固定剂量组合用于慢性心力衰竭治疗，它最近引起了关注。本综述阐明了 neprilysin 在心脏肾脏疾病中的作用、其病理生理学以及 NEP 抑制的益处。它还总结了 NEP 抑制剂（NEPi）及其结构-活性关系的研究进展。此外，该综述深入探讨了 NEPi 的疗效——单独使用或与其他心脏肾脏保护剂联合使用。预计这将有助于药物化学家合成和开发新型 NEPi。
