7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶作为人嗜酸性粒细胞磷酸二酯酶的新型抑制剂。

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

作者信息

Duplantier A J, Andresen C J, Cheng J B, Cohan V L, Decker C, DiCapua F M, Kraus K G, Johnson K L, Turner C R, UmLand J P, Watson J W, Wester R T, Williams A S, Williams J A

机构信息

Central Research Division, Pfizer Inc, Groton, Connecticut 06340, USA.

出版信息

J Med Chem. 1998 Jun 18;41(13):2268-77. doi: 10.1021/jm9800090.

DOI:10.1021/jm9800090

PMID:9632360

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).

摘要

通过针对人肺磷酸二酯酶4（PDE4）抑制作用的高通量药物筛选，发现了3-乙基-1-（4-氟苯基）-6-苯基-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶（11）作为一种新型PDE4抑制剂。随后利用嗜酸性粒细胞PDE检测进行的构效关系（SAR）研究，得到了比11活性高50倍的类似物，其IC50值为0.03 - 1.6微摩尔。其中一种化合物CP-220,629（22）（IC50 = 0.44微摩尔），在豚鼠雾化抗原诱导的气道阻塞试验中有效（ED50 2.0毫克/千克，口服），并且在特应性猴子中（10毫克/千克，口服）对抗原攻击的嗜酸性粒细胞（55%）、中性粒细胞（65%）和白细胞介素-1β（82%）反应有显著降低。