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 l ed to the discovery of -oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyrid ine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent th an 11 with IC50 values of 0.03-1.6 mu M. One such compound, CP-220,629 (22) (IC50 = 0.44 mu M), was efficacious in the guinea pig aerosolize d antigen induced airway obstruction assay (ED50 2.0 mg/kg, po) and de monstrated a significant reduction in eosinophil (55%), neutrophil (65 %), and IL-1 beta (82%) responses to antigen challenge in atopic monke ys (10 mg/kg, po).