Ashton M J, Cook D C, Fenton G, Karlsson J A, Palfreyman M N, Raeburn D, Ratcliffe A J, Souness J E, Thurairatnam S, Vicker N
Rhône-Poulenc Rorer Central Research, Dagenham Research Centre, Essex, England.
J Med Chem. 1994 May 27;37(11):1696-703. doi: 10.1021/jm00037a021.
The syntheses and biological activities of a number of benzamide derivatives, designed from rolipram, which are selective inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), are described. The effects of changes to the alkoxy groups, amide linkage, and benzamide N-phenyl ring on the inhibition of the cytosolic PDE IV from pig aorta have been investigated. As a result, some highly potent and selective PDE IV inhibitors have been identified. The most potent compounds have been further evaluated for their inhibitory potencies against PDE IV obtained from and superoxide O2- generation from guinea pig eosinophils in vitro. Selected compounds have also been examined for their activities in inhibiting histamine-induced bronchospasm in anaesthetized guinea pigs. 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (15j) showed exceptional potency in all tests and may have therapeutic potential in the treatment of asthma.
本文描述了一系列从咯利普兰设计而来的苯甲酰胺衍生物的合成及其生物活性，这些衍生物是环磷酸腺苷特异性磷酸二酯酶（PDE IV）的选择性抑制剂。研究了烷氧基、酰胺键和苯甲酰胺N-苯环的变化对猪主动脉胞质PDE IV抑制作用的影响。结果，鉴定出了一些高效且选择性的PDE IV抑制剂。对最有效的化合物进一步评估了其对豚鼠嗜酸性粒细胞中PDE IV的抑制效力以及体外超氧化物O2-的生成。还检测了所选化合物在麻醉豚鼠中抑制组胺诱导的支气管痉挛的活性。3-(环戊氧基)-N-(3,5-二氯-4-吡啶基)-4-甲氧基苯甲酰胺（15j）在所有测试中均表现出卓越的效力，可能在哮喘治疗中具有治疗潜力。
