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  • Review Article
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Phosphodiesterase 5 inhibitors: current status and potential applications

Nature Reviews Drug Discovery volume 1, pages 674–682 (2002)Cite this article

Key Points

  • Phosphodiesterase 5 (PDE5) inhibitors are useful for the treatment of erectile dysfunction (ED), and a wide variety of chemotypes have shown activity as PDE5 inhibitors.

  • PDE5 inhibitors work in conjunction with sexual stimulation to induce erection, and have a low risk of priaprism.

  • Clinical studies with sildenafil, vardenafil and tadalafil indicate that these compounds are efficacious for the treatment of ED that is a consequence of various causes, and are safe for use in most patients.

  • Vardenafil and tadalafil have been submitted for regulatory approval in the US and European markets. Final approval and marketing of these compounds is pending the outcome of regulatory review.

  • There is substantial activity in the discovery of novel PDE5 inhibitors, some of which are more potent and selective than sildenafil in vitro.

  • PDE5 inhibitors have also been investigated for actions on other tissues, including the gastrointestinal tract and the circulatory system. PDE5 inhibitors have been shown to reduce blood pressure in patients with pulmonary hypertension, and in animal models, have potential for use in the treatment of stroke.

Abstract

Phosphodiesterase enzymes convert cyclic GMP and cyclic AMP to the corresponding nucleotide monophosphates. Phosphodiesterase 5 (PDE5) inhibition is now a widely accepted and efficacious therapeutic option for the treatment of erectile dysfunction in men, as a result of extensive clinical experience with sildenafil and other new PDE5 inhibitors. Research in the field continues at a substantial level to identify new, selective PDE5 inhibitors and to investigate their usefulness and activity in other areas. This review summarizes recent clinical trials with PDE5 inhibitors, advances in medicinal chemistry, and other activities and potential applications of this class of compounds.

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Figure 1: PDE5 inhibitors.
Figure 2: Cellular mechanism of action of PDE5 inhibitors.
Figure 3: PDE5 inhibition by pyrimidine isosteres.
Figure 4: PDE5 inhibitors that are structurally unrelated to sildenafil.
Figure 5: PDE5 inhibitors based on the structure of sildenafil.
Figure 6: Novel pyrazolopyridine PDE5 inhibitors.
Figure 7: PDE5 inhibitors based on pyrazolopyridopyridazine.

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Acknowledgements

The assistance of V. Florio and K. Fowler in the preparation of this review is gratefully acknowledged.

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Authors and Affiliations

  1. Hopewell Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 5400, Princeton, 08543-5400, New Jersey, USA

    David P. Rotella

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DATABASES

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CYP2D6

HERG

PDE1

PDE2

PDE3

PDE4

PDE5

PDE6

PDE7

PDE8

PDE9

PDE10

PDE11

PKA

PKG

soluble guanylyl cyclase

xanthine oxidase

Medscape DrugInfo

milrinone

mirtazapine

sildenafil

OMIM

cystic fibrosis

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Glossary

CORPUS CAVERNOSUM

The vascular space in erectile tissue.

PENDANT

A functional group that is attached to another in a molecule.

HYDROPATHY

The analysis of the hydrophobic and hydrophilic characteristics of molecules.

HAEMODYNAMIC

Relating to physical aspects of blood circulation.

PRIAPRISM

A persistent erection of the penis resulting from causes other than sexual stimulation.

PLETHYSMOGRAPHY

The measurement and recording of changes in volume of an organ or structure.

TUMESCENCE

Becoming swollen.

ISOSTERE

Isosteres are atoms or functional groups of similar size and molecular orientation relative to each other.

HETEROATOMS

Atoms other than carbon or hydrogen in a molecule.

TORSIONAL

The freedom or ability to rotate along a defined angle.

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Rotella, D. Phosphodiesterase 5 inhibitors: current status and potential applications. Nat Rev Drug Discov 1, 674–682 (2002). https://doi.org/10.1038/nrd893

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