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

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.

Figure 1. The NO/cGMP signalling pathway.

The figure shows stimuli promoting the synthesis of cGMP, downstream intracellular signalling targets modulated by cGMP and the role of phosphodiesterases (PDEs) in cGMP breakdown. This pathway mediates relaxation of vascular smooth muscle and penile erection (only upon sexual stimulation) and pulmonary vasodilatation (continuously). Smooth muscle relaxation is in part mediated via protein kinase G (PKG) activation, subsequent potassium channel opening and reductions in intracellular calcium levels. PDE5 is the target for sildenafil and other PDE5 inhibitors in the treatment of chronic vascular disorders. cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide.

Figure 2. Working model of PDE5.

The regulatory domain in the amino-terminal portion of PDE5 contains a phosphorylation site and two allosteric cGMP-binding sites, a and b, that are theorized to be involved in a cGMP negative-feedback loop. The catalytic domain in the carboxyl-terminal portion contains two Zn²⁺-binding motifs, A and B, and a cGMP-binding substrate site. cGMP, cyclic guanosine monophosphate; PDE5, phospho-diesterase type 5. Reproduced, with permission, from Ref. © (1999) American Society for Biochemistry and Molecular Biology.

Figure 3. Comparison of the structures of cGMP, sildenafil and other PDE5 inhibitors.

a | The native substrate, cGMP. b | Sildenafil. c | Vardenafil and Tadalafil. cGMP, cyclic guanosine monophosphate; PDE5, phospho-diesterase type 5.

Figure 4. Structure of the PDE5 catalytic domain.

X-ray crystallography undertaken at the Pfizer Sandwich laboratories has been used to solve the first atomic structure of the PDE5 catalytic domain^,. PDE5 has a globular structure and possesses a deep cleft, the GMP-binding site. The figure illustrates the binding of the UK-92,480 at the catalytic site of PDE5 with a surface representation of the protein coloured according to electrostatic charge. PDE5, phosphodiesterase type 5.

Timeline | Milestones in the development of sildenafil for erectile dysfunction and pulmonary hypertension

Figure 5. Adaptation of blood flow to ventilation in the pulmonary circulation.

Blood flow (Q) in the pulmonary circulation must, ideally, be directed to well-ventilated areas (symbolized by big V (ventilation) and O₂ (oxygenation) in the largest alveolus (blue circle at bottom of figure)) to ensure optimized gas exchange ('matching'), whereas only a small amount of blood should flow through areas of minor or no ventilation (midsize and small alveolus, respectively) (left panel). Lung vessel dilatation is mainly regulated by the compartmentalized production of nitric oxide (NO) and subsequent intracellular cGMP formation, where alveolar distension and oxygenation represent the most potent stimuli for this local NO release. Similarly, less NO/cGMP is produced in non-ventilated areas of the lung, resulting in hypoxic vasoconstriction (the so called von Euler–Liljestrand mechanism). During application of non-selective vasodilators and/or under disease conditions (for example, chronic obstructive lung disease, lung fibrosis, sepsis or acute respiratory distress syndrome), vasodilatation is induced in poorly or non-ventilated areas of the lung resulting in venous admixture and worsening of gas-exchange ('mismatch', right panel). There is strong evidence that oral sildenafil preferentially dilates vessels in well-ventilated areas of the lung, thereby both reducing overall vascular resistance and improving overall oxygenation ('re-matching' drug)^,.