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

Autor:	Ron Sarver, Christopher Whitehead, Heidi Baum, James Hicks, Richard Gowan, Brian Sanchez, Xiao Kang Lu, Susan E. Bove, Joseph A. Cornicelli, Howard Miller, Sandra Lightle, Aurash B Shahripour, Katherine Welch, Craig Banotai, Jayvardhan Pandit, Mark S. Plummer, Timothy Braden, David Beidler, Adam Ogden, Skalitzky Donald James, Annise Paige Goodman, Howard Roark, Nalini Sadagopan, Charles J. Stankovic, Cindy Spessard, Xi Qiang Shen
Rok vydání:	2013
Předmět:	Dihydropyridines Phosphodiesterase Inhibitors Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Osteoarthritis Plasma protein binding Pharmacology Crystallography X-Ray Biochemistry Structure-Activity Relationship Catalytic Domain Drug Discovery medicine Animals Structure–activity relationship Binding site Molecular Biology chemistry.chemical_classification Binding Sites biology Azirines Chemistry fungi Organic Chemistry Active site medicine.disease Cyclic Nucleotide Phosphodiesterases Type 2 Cyclic Nucleotide Phosphodiesterases Type 4 Disease Models Animal Transformation (genetics) Enzyme biology.protein Molecular Medicine Phosphodiesterase 2 Phosphodiesterase 4 Inhibitors Protein Binding
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 23:3438-3442
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2013.03.072
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::128c0eb423facb1ebd01be1c3f41f3b1 https://doi.org/10.1016/j.bmcl.2013.03.072 Zobrazit plný text záznamu Full Text from ScienceDirect