Abstract
High-throughput file screening against inhibition of human lung PDE4 led to the discovery of 3-ethyl-1-(4-fluorophenyl)-6-phenyl-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent than 11 with IC50 values of 0.03-1.6 microM. One such compound, CP-220,629 (22) (IC50 = 0.44 microM), was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 2.0 mg/kg, po) and demonstrated a significant reduction in eosinophil (55%), neutrophil (65%), and IL-1beta (82%) responses to antigen challenge in atopic monkeys (10 mg/kg, po).
MeSH terms
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Airway Obstruction / immunology
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Airway Obstruction / metabolism
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Airway Obstruction / pathology
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Airway Obstruction / prevention & control
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Animals
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Anti-Asthmatic Agents* / chemical synthesis
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Anti-Asthmatic Agents* / chemistry
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Anti-Asthmatic Agents* / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal* / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal* / chemistry
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Anti-Inflammatory Agents, Non-Steroidal* / pharmacology
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Bronchoalveolar Lavage Fluid / cytology
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Bronchoalveolar Lavage Fluid / immunology
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Cell Count / drug effects
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Cell Line
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Cyclic AMP / metabolism
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Cytokines / metabolism
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Dihydropyridines* / chemical synthesis
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Dihydropyridines* / chemistry
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Dihydropyridines* / pharmacology
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Drug Evaluation, Preclinical
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Eosinophils / drug effects
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Eosinophils / enzymology*
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Eosinophils / immunology
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Guinea Pigs
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Humans
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In Vitro Techniques
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Isoenzymes / antagonists & inhibitors*
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Macaca fascicularis
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Molecular Conformation
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Neutrophils / drug effects
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Neutrophils / immunology
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Ovalbumin / immunology
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Phosphodiesterase Inhibitors* / chemical synthesis
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Phosphodiesterase Inhibitors* / chemistry
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Phosphodiesterase Inhibitors* / pharmacology
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Phosphoric Diester Hydrolases / metabolism*
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Pyrazoles* / chemical synthesis
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Pyrazoles* / chemistry
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Pyrazoles* / pharmacology
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Pyrrolidinones / pharmacology
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Rolipram
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Structure-Activity Relationship
Substances
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Anti-Asthmatic Agents
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Anti-Inflammatory Agents, Non-Steroidal
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Cytokines
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Dihydropyridines
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Isoenzymes
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Phosphodiesterase Inhibitors
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Pyrazoles
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Pyrrolidinones
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Ovalbumin
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CP 220629
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Cyclic AMP
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Phosphoric Diester Hydrolases
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Rolipram