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

1998; American Chemical Society; Volume: 41; Issue: 13 Linguagem: Inglês

10.1021/jm9800090

1520-4804

Allen J. Duplantier, Catharine J. Andresen, John B. Cheng, Victoria L. Cohan, Christian Decker, Frank M. DiCapua, Kenneth G. Kraus, Kerry L. Johnson, Claudia R. Turner, John P. Umland, J. W. Watson, Ronald T. Wester, Alison S. Williams, John A. Williams,

Synthesis and Catalytic Reactions

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).