Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED

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Abstract

In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.

Graphical abstract

In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.

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Acknowledgements

The authors wish to thank Professor Ronald Breslow, Dr. John Hunter, Dr. John Piwinski, and Dr. Catherine Strader for helpful discussions. We also thank Dr. Pradip Das for obtaining analytical data.

References and notes (17)

  • H. Haning et al.

    Prog. Med. Chem.

    (2003)
  • S.A. Ballard et al.

    J. Urol.

    (1998)
  • Y. Wang et al.

    Bioorg. Med. Chem. Lett.

    (2002)
  • A.J. Carter et al.

    J. Urol.

    (1998)
  • D.A. Pissarnitski et al.

    Bioorg. Med. Chem. Lett.

    (2004)
  • N.K. Terett et al.

    Bioorg. Med. Chem. Lett.

    (1996)
  • G.M. Keating et al.

    Drugs

    (2003)
  • M.P. Curran et al.

    Drugs

    (2003)
There are more references available in the full text version of this article.

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