2. Academic Validation
  3. Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, part I: transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors

Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, part I: transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors

  • Bioorg Med Chem Lett. 2013 Jun 1;23(11):3438-42. doi: 10.1016/j.bmcl.2013.03.072.
Mark S Plummer 1,  Joseph Cornicelli,  Howard Roark,  Donald J Skalitzky,  Charles J Stankovic,  Susan Bove,  Jayvardhan Pandit,  Annise Goodman,  James Hicks,  Aurash Shahripour,  David Beidler,  Xiao Kang Lu,  Brian Sanchez,  Christopher Whitehead,  Ron Sarver,  Timothy Braden,  Richard Gowan,  Xi Qiang Shen,  Katherine Welch,  Adam Ogden,  Nalini Sadagopan,  Heidi Baum,  Howard Miller,  Craig Banotai,  Cindy Spessard,  Sandra Lightle
Affiliations

Affiliation

  • 1 Department of Chemistry, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. marksplummer@gmail.com
PMID: 23582272 DOI: 10.1016/j.bmcl.2013.03.072
Abstract

We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 Enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition.

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