7-Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridines as Novel Inhibitors of Human Eosinophil Phosphodiesterase

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-fo...

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Veröffentlicht in:	Journal of medicinal chemistry 1998-06, Vol.41 (13), p.2268-2277
Hauptverfasser:	Duplantier, Allen J, Andresen, Catharine J, Cheng, John B, Cohan, Victoria L, Decker, Christian, DiCapua, Frank M, Kraus, Kenneth G, Johnson, Kerry L, Turner, Claudia R, UmLand, John P, Watson, John W, Wester, Ronald T, Williams, Alison S, Williams, John A
Format:	Artikel
Sprache:	eng
Schlagworte:	Airway Obstruction - immunology Airway Obstruction - metabolism Airway Obstruction - pathology Airway Obstruction - prevention & control Animals Anti-Asthmatic Agents - chemical synthesis Anti-Asthmatic Agents - chemistry Anti-Asthmatic Agents - pharmacology Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacology Bronchoalveolar Lavage Fluid - cytology Bronchoalveolar Lavage Fluid - immunology Cell Count - drug effects Cell Line Cyclic AMP - metabolism Cytokines - metabolism Dihydropyridines - chemical synthesis Dihydropyridines - chemistry Dihydropyridines - pharmacology Drug Evaluation, Preclinical Eosinophils - drug effects Eosinophils - enzymology Eosinophils - immunology Guinea Pigs Humans In Vitro Techniques Isoenzymes - antagonists & inhibitors Macaca fascicularis Molecular Conformation Neutrophils - drug effects Neutrophils - immunology Ovalbumin - immunology Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - chemistry Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - metabolism Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Pyrrolidinones - pharmacology Rolipram Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	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 μM. One such compound, CP-220,629 (22) (IC50 = 0.44 μM), 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-1β (82%) responses to antigen challenge in atopic monkeys (10 mg/kg, po).
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm9800090