Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: Optimization studies and demonstration of in vivo efficacy
| Autor: | Skalitzky Donald James, Craig Banotai, Jayvardhan Pandit, Adam Ogden, James Hicks, Annise Paige Goodman, Xiao Kang Lu, Howard Miller, Howard Roark, Susan E. Bove, Sandra Lightle, Aurash B Shahripour, Timothy Braden, Mark S. Plummer, Katherine Welch, Charles J. Stankovic, Ron Sarver, Joseph A. Cornicelli, Christopher Whitehead, Brian Sanchez, Nalini Sadagopan, Heidi Baum, Richard Gowan, David Beidler, Xi Qiang Shen, Cindy Spessard |
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| Rok vydání: | 2013 |
| Předmět: |
Dihydropyridines
Phosphodiesterase Inhibitors Clinical Biochemistry Analgesic Drug Evaluation Preclinical Pharmaceutical Science Pharmacology Crystallography X-Ray Biochemistry law.invention Structure-Activity Relationship Pharmacokinetics law In vivo Catalytic Domain Osteoarthritis Drug Discovery Animals Structure–activity relationship Molecular Biology chemistry.chemical_classification Analgesics Binding Sites Azirines fungi Organic Chemistry Azepines Cyclic Nucleotide Phosphodiesterases Type 2 Rats Bioavailability Disease Models Animal Enzyme chemistry Recombinant DNA Pyrazoles Molecular Medicine Phosphodiesterase 2 Phosphodiesterase 4 Inhibitors Half-Life Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:3443-3447 |
| ISSN: | 0960-894X |
| Popis: | Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose. |
| Databáze: | OpenAIRE |
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