Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond

Key Points

  • 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.

Abstract

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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Figure 1: The NO/cGMP signalling pathway.
Figure 2: Working model of PDE5.
Figure 3: Comparison of the structures of cGMP, sildenafil and other PDE5 inhibitors.
Figure 4: Structure of the PDE5 catalytic domain.
Figure 5: Adaptation of blood flow to ventilation in the pulmonary circulation.

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Acknowledgements

Our gratitude goes to R. Schermuly, N. Weissmann and R. Morty (from the University of Giessen Lung Center (UGLC)) and to G. Butrous, D. Brown and C. Wayman (from Pfizer Ltd., Sandwich) for thorough linguistic editing, helpful comments and input to the manuscript. This work was supported by the German research foundation (DFG; Sonderforschungsbereich 547).

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Correspondence to Hossein A. Ghofrani.

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Competing interests

H.A.G. has received honoraria for invited lectures from Schering AG, Altana Pharma, Pfizer, Actelion, CoTherix and United Therapeutics. H.A.G. is also a consultant to Altana Pharma, Schering AG, Pfizer, Novartis, Actelion and CoTehrix. H.A.G. has received unrestricted research grants from Altana Pharma and Pfizer. H.A.G. holds no stocks or shares of any of the aforementioned companies.

I.O. was responsible for the clinical development of Viagra for erectile dysfunction and is still a full-time employe of Pfizer Ltd (the manufacturer of Viagra). I.O. also holds shares in Pfizer.

F.G. has received honoraria for invited lectures from Schering AG, Altana Pharma and Pfizer. F.G. is also a consultant to Altana Pharma, Pfizer and Schering AG. F.G. has received unrestricted research grants from Altana Pharma, Bayer and Pfizer. F.G. holds no stocks or shres of any of the aforementioned companies.

Glossary

Angina pectoris

Severe chest pains caused by insufficient supply of blood to the heart.

Tachyphylaxis

Reduced responsiveness to a drug that is chronically supplied and requires dose up-titration to maintain the same level of efficacy over time.

Corpus cavernosum

An expandable erectile tissue along the length of the penis, which fills with blood during male erection.

Pulmonary hypertension

Increased blood pressure (>25 mm Hg at rest and >30 mm Hg for the mean pulmonary arterial pressure) in lung vessels.

Alveolar hypoxia

Reduced oxygen levels (<80 mm Hg) in the lung alveoli caused by impaired ventilation (for example, in chronic lung disorders) or reduced oxygen content in the inspired air (for example, at high altitudes).

Hypoxic pulmonary vasoconstriction

Constriction of pulmonary vessels in the presence of alveolar hypoxia, which prevents the perfusion of non-ventilated areas of lung and maintains optimized gas-exchange properties (also known as the von Euler–Liljestrand mechanism).

Exercise tolerance

Ability to perform physical strain until limited by occurrence of peripheral (muscular) exhaustion, shortness of breath and/or insufficient blood supply to the myocardium (due, for example, to coronary heart disease).

Neurovascular coupling

Mechanism by which local blood flow in the brain is adapted to underlying neuronal activity in a fast and fine-tuned manner.

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Ghofrani, H., Osterloh, I. & Grimminger, F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 5, 689–702 (2006). https://doi.org/10.1038/nrd2030

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