Brackeen M F, Cowan D J, Stafford J A, Schoenen F J, Veal J M, Domanico P L, Rose D, Strickland A B, Verghese M, Feldman P L
Glaxo Wellcome Research, Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 1995 Nov 24;38(24):4848-54. doi: 10.1021/jm00024a012.
The synthesis and biological evaluation of cAMP-specific phosphodiesterase (PDE IV) inhibitors is described. The PDE IV inhibitor 4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one (Ro 20-1724, 2) was used as a template from which to design a set of rigid oxazolidinones, imidazolidinones, and pyrrolizidinones that mimic Ro 20-1724 but differ in the orientation of the carbonyl group. The endo isomer of each of these heterocycles was more potent than the exo isomer in an enzyme inhibition assay and a cellular assay, which measured TNF alpha secretion from activated human peripheral blood monocytes (HPBM). Imidazolidinone 4a inhibited human PDE IV with a Ki of 27 nM and TNF alpha secretion from HPBM with an IC50 of 290 nM. By comparison, Ro 20-1724 is significantly less active in these assays with activities of 1930 and 1800nM, respectively.
本文描述了环磷酸腺苷特异性磷酸二酯酶（PDE IV）抑制剂的合成及生物学评价。以PDE IV抑制剂4-(3-丁氧基-4-甲氧基苄基)咪唑烷-2-酮（Ro 20-1724，2）为模板，设计了一组刚性恶唑烷酮、咪唑烷酮和吡咯里西啶酮，它们模仿Ro 20-1724，但羰基的取向不同。在酶抑制试验和细胞试验中，这些杂环化合物的内型异构体比外型异构体更具活性，细胞试验测量了活化的人外周血单核细胞（HPBM）分泌的肿瘤坏死因子α（TNFα）。咪唑烷酮4a抑制人PDE IV的Ki为27 nM，抑制HPBM分泌TNFα的IC50为290 nM。相比之下，Ro 20-1724在这些试验中的活性明显较低，其活性分别为1930和1800 nM。
