Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China.
Department of Chemistry, Graduate School of Science Kyoto University Kitashirakawa- Oiwakecho, Sakyo-Ku, kyoto, Japan.
Mini Rev Med Chem. 2019;19(18):1544-1557. doi: 10.2174/1389557519666190730110600.
Soluble Guanylate Cyclase (sGC) is the intracellular receptor of Nitric Oxide (NO). The activation of sGC results in the conversion of Guanosine Triphosphate (GTP) to the secondary messenger cyclic Guanosine Monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as Phosphodiesterase (PDE), Protein Kinase G (PKG) and Cyclic Nucleotide-Gated Ion Channels (CNG). NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. With the approval of an sGC stimulator Riociguat for the treatment of Pulmonary Arterial Hypertension (PAH), the enthusiasm in the discovery of sGC modulators continues for broad clinical applications. Notably, through activating the NO-sGC-cGMP pathway, sGC stimulator and activator potentiate for the treatment of various diseases, such as PAH, Heart Failure (HF), Diabetic Nephropathy (DN), Systemic Sclerosis (SS), fibrosis as well as other diseases including Sickle Cell Disease (SCD) and Central Nervous System (CNS) disease. Here, we review the preclinical and clinical studies of sGC stimulator and activator in recent years and prospect for the development of sGC modulators in the near future.
可溶性鸟苷酸环化酶（sGC）是一氧化氮（NO）的细胞内受体。sGC 的激活导致鸟苷三磷酸（GTP）转化为第二信使环鸟苷酸（cGMP）。cGMP 通过激活各种效应物，如磷酸二酯酶（PDE）、蛋白激酶 G（PKG）和环核苷酸门控离子通道（CNG），调节一系列下游级联反应。NO-sGC-cGMP 途径在各种生理过程中发挥重要作用，包括血小板聚集、平滑肌松弛和神经递质传递。随着 sGC 刺激剂 Riociguat 被批准用于肺动脉高压（PAH）的治疗，人们对 sGC 调节剂的发现热情持续高涨，以期广泛应用于临床。值得注意的是，通过激活 NO-sGC-cGMP 途径，sGC 刺激剂和激活剂增强了治疗各种疾病的作用，如 PAH、心力衰竭（HF）、糖尿病肾病（DN）、系统性硬化症（SS）、纤维化以及其他疾病，包括镰状细胞病（SCD）和中枢神经系统（CNS）疾病。在这里，我们回顾了近年来 sGC 刺激剂和激活剂的临床前和临床研究，并对 sGC 调节剂的近期发展进行了展望。
