7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridines as novel inhibitors of human eosinophil phosphodiesterase

被引：34

作者：

Duplantier, AJ ^{[1
]}

Andresen, CJ ^{[1
]}

Cheng, JB ^{[1
]}

Cohan, VL ^{[1
]}

Decker, C ^{[1
]}

DiCapua, FM ^{[1
]}

Kraus, KG ^{[1
]}

Johnson, KL ^{[1
]}

Turner, CR ^{[1
]}

Umland, JP ^{[1
]}

Watson, JW ^{[1
]}

Wester, RT ^{[1
]}

Williams, AS ^{[1
]}

Williams, JA ^{[1
]}

机构：

[1] Pfizer Inc, Div Cent Res, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 13期

关键词：

D O I：

10.1021/jm9800090

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M. One such compound, CP-220,629 (22) (IC50 = 0.44 mu M), 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-1 beta (82%) responses to antigen challenge in atopic monkeys (10 mg/kg, po).

引用

页码：2268 / 2277

页数：10

共 19 条

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