Collins P W, Gasiecki A F, Weier R M, Kramer S W, Jones P H, Gullikson G W, Bianchi R G, Bauer R F
Gastrointestinal Diseases Research Department, G.D. Searle & Co., Skokie, IL 60077.
Prostaglandins. 1987;33 Suppl:17-28. doi: 10.1016/0090-6980(87)90045-1.
Misoprostol, a 15-deoxy-16-hydroxy-16-methyl analog of PGE1, is an effective agent for the treatment of peptic ulcer disease. Efforts to impede metabolic degradation of the alpha chain of misoprostol led to the discovery of a second clinical candidate in this series. Enisoprost, a delta 4Z derivative of misoprostol, is more potent as a gastric antisecretory agent and longer acting than misoprostol. These findings prompted further work to determine the effects that two double bonds in the alpha chain might have on the activity profile of misoprostol. The most promising structure in this series was a 1:1 mixture of 3E,5Z and 3Z,5Z dienes which was about three times more potent than misoprostol in inhibiting gastric secretion in dogs, while the separation of the diarrheogenic effect was significantly improved. Chromatographic separation of the mixture was very difficult, but small amounts of each isomer were obtained by HPLC, and preliminary antisecretory studies indicated that most of the activity resided in the 3E,5Z isomer. A stereospecific synthesis of the 3E,5Z isomer was carried out to provide sufficient quantities for complete pharmacological assessment. The 3E,5Z diene was about three times more potent than misoprostol in inhibiting gastric acid secretion in dogs and also in producing diarrhea in rats.
米索前列醇是PGE1的15 - 脱氧 - 16 - 羟基 - 16 - 甲基类似物，是治疗消化性溃疡疾病的有效药物。为了阻止米索前列醇α链的代谢降解所做的努力，促成了该系列中的第二个临床候选药物的发现。依索前列醇是米索前列醇的δ4Z衍生物，作为胃抗分泌剂比米索前列醇更有效且作用时间更长。这些发现促使进一步研究，以确定α链中的两个双键可能对米索前列醇活性谱产生的影响。该系列中最有前景的结构是3E,5Z和3Z,5Z二烯的1:1混合物，其在抑制犬胃酸分泌方面比米索前列醇强约三倍，同时致腹泻作用的分离得到显著改善。混合物的色谱分离非常困难，但通过高效液相色谱法获得了少量的每种异构体，初步抗分泌研究表明大部分活性存在于3E,5Z异构体中。进行了3E,5Z异构体的立体定向合成，以提供足够数量用于完整的药理学评估。3E,5Z二烯在抑制犬胃酸分泌以及在大鼠中引起腹泻方面比米索前列醇强约三倍。
