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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 |
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| Authors: | Mark S. Plummer 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 Sandra Lightle |
| Affiliation: | 1. Department of Chemistry, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA;2. Inflammation Pharmacology, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA;3. Discovery Technology, Pfizer Global Research and Development, Groton CT 06340, USA;4. Pharmacodynamics and Drug Metabolism, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA;5. Discovery Technology, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA |
| 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. |
| Keywords: | Phosphodiesterase 2 (PDE2)inhibition Structure-based drug design Osteoarthritis(OA)pain |
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