Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond.
Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond.
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DOI：
10.1038/nrd2030
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发表时间：
2006-08
期刊：
影响因子：
--
通讯作者：
Grimminger F
中科院分区：
文献类型：
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作者：
Ghofrani HA;Osterloh IH;Grimminger F
一氧化氮（NO）是神经和血流动力学作用的关键介质。NO扩散到血管平滑肌细胞，刺激cGMP的产生，导致血管舒张。NO/cGMP的作用受到磷酸二酯酶5 （PDE5）的限制，PDE5使cGMP失活，存在于血管平滑肌和血小板中。1986年，作为心绞痛药物研究项目的一部分，辉瑞实验室发现新型吡唑嘧啶是PDE5的高效抑制剂。一种最初被命名为uk - 92480，但现在更广为人知的是西地那非的化合物，被证明对PDEs1-4具有非常好的效力和良好的选择性。在20世纪80年代，对勃起功能障碍（ED）的认识和治疗取得了进展，导致了通过调节cAMP水平起作用的药物的使用。然而，缺点包括治疗的侵入性，诱导“人工”勃起和许多副作用。在20世纪90年代早期，西地那非作为心绞痛治疗药物的前景并不乐观。同时，实验和临床研究证明PDE5抑制可能是ED的一种有吸引力的治疗方法，因为NO是海绵体血管张力的关键调节剂。到1997年，21个独立的临床试验证明了西地那非对不同患者群体的疗效。1998年3月，FDA批准伟哥用于治疗ED。欧洲于1998年9月批准。肺动脉高压是一种具有不同起源的毁灭性疾病，其中特发性肺动脉高压（iPAH）最具特征。在20世纪90年代初，静脉注射前列环素被引入作为iPAH的第一个特异性治疗；然而，这种疗法受到各种缺陷的阻碍。灌注分布在肺通风良好区域的适应是由局部NO/ cGMP信号调节的。PDE5在肺组织中大量表达，因此是治疗肺循环疾病的理想靶点。1998年至2001年间，越来越多的证据表明西地那非治疗肺血管疾病的疗效，并导致设计了一项大型随机、对照、多国试验，即SUPER-1研究。西地那非于2005年被FDA和EMEA批准用于治疗多环芳烃。目前正在研究的新的潜在适应症包括治疗与潜在肺部疾病相关的肺动脉高压（例如，慢性阻塞性肺疾病和纤维化）、慢性血栓栓塞性肺动脉高压、雷诺现象、左右心室肥厚和脑血管疾病。磷酸二酯酶5抑制剂增强内源性一氧化氮信号，从而恢复血管对病变血管的反应性。Ghofrani及其同事回顾了PDE5抑制剂西地那非从一种潜在的抗心绞痛药物到一种治疗勃起功能障碍的按需口服药物的演变，以及它最近重新定位为肺动脉高压的治疗药物。在不到20年的时间里，第一种选择性5型磷酸二酯酶抑制剂西地那非已经从一种潜在的抗心绞痛药物发展成为一种治疗勃起功能障碍的按需口服药物（伟哥），最近又发展成为一种治疗肺动脉高压的口服药物（Revatio）。在这里，我们描述了西地那非在这些不同医疗条件下发展的关键里程碑，讨论了伴随这一旅程的科学和临床医学的进步，并考虑了这种多功能药物未来可能的适应症。
Nitric oxide (NO) is a key mediator of neural and haemodynamic effects. NO diffuses into vascular smooth muscle cells, stimulating the production of cGMP and leading to vasodilatation. The effects of NO/cGMP are limited by phosphodiesterase 5 (PDE5), which inactivates cGMP and is present in the smooth muscle of the vasculature and in platelets. In 1986, novel pyrazolopyrimidines were identified as highly potent inhibitors of PDE5 at Pfizer laboratories as part of a programme seeking drugs for angina pectoris. A compound initially named UK-92,480, but now better known as sildenafil, was demonstrated to have very good potency and excellent selectivity over PDEs1–4. During the 1980s, advances in the recognition and treatment of erectile dysfunction (ED), led to the use of drugs that function by modulating cAMP levels. However, drawbacks included the invasive nature of the treatment, induction of an 'artificial' erection and numerous side effects. In the early 1990s sildenafil was looking less promising as an angina therapeutic. At the same time, experimental and clinical studies provided evidence that PDE5 inhibition might be an attractive therapeutic approach to ED, as NO is a key regulator of vascular tone in the corpus cavernosum. By 1997, 21 separate clinical trials had demonstrated the efficacy of sildenafil in various patient populations. The FDA approved VIAGRA for the treatment of ED in March 1998. European approval followed in September 1998. Pulmonary hypertension is a devastating disease of different origins of which the idiopathic form of pulmonary arterial hypertension (iPAH) is the best characterized. In the early 1990s, intravenous prostacyclin was introduced as the first specific treatment for iPAH; however, this therapy is hampered by various drawbacks. Adaptation of perfusion distribution to well-ventilated areas of the lung is regulated by local NO/ cGMP signalling. PDE5 is abundantly expressed in lung tissue and is therefore an ideal target for the treatment of disorders in the pulmonary circulation. Between 1998–2001, growing evidence demonstrated the efficacy of sildenafil in the treatment of pulmonary vascular disorders and led to the design of a large randomized, controlled, multinational trial, the SUPER-1 study. Sildenafil was approved by the FDA and the EMEA in 2005 for the treatment of PAH. New potential indications currently under investigation include the treatment of pulmonary hypertension associated with underlying lung diseases (for example, chronic obstructive pulmonary disease and fibrosis), chronic thromboembolic pulmonary hypertension, Raynaud's phenomenon, right- and left-ventricular hypertrophy, and cerebrovascular diseases. Phosphodiesterase 5 inhibitors augment endogenous nitric oxide signalling, thereby restoring vascular reactivity to diseased blood vessels. Ghofrani and colleagues review the evolution of the PDE5 inhibitor sildenafil from a potential anti-angina drug, to an on-demand oral treatment for erectile dysfunction, and its recent re-positioning as a pulmonary hypertension therapeutic. In less than 20 years, the first selective type 5 phosphodiesterase inhibitor, sildenafil, has evolved from a potential anti-angina drug to an on-demand oral treatment for erectile dysfunction (Viagra), and more recently to a new orally active treatment for pulmonary hypertension (Revatio). Here we describe the key milestones in the development of sildenafil for these diverse medical conditions, discuss the advances in science and clinical medicine that have accompanied this journey and consider possible future indications for this versatile drug.
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