Congiu Cenzo, Onnis Valentina, Deplano Alessandro, Salvadori Severo, Marconi Veronica, Maftei Daniela, Negri Lucia, Lattanzi Roberta, Balboni Gianfranco
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, I-09124 Cagliari, Italy.
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, I-09124 Cagliari, Italy.
Eur J Med Chem. 2014 Jun 23;81:334-40. doi: 10.1016/j.ejmech.2014.05.030. Epub 2014 May 14.
A new efficient synthetic method to obtain prokineticin receptor antagonists based on the triazinedione scaffold is described. In this procedure the overall yield improves from 13% to about 54%, essentially for two factors: 1) N-(chlorocarbonyl) isocyanate is no more used, it represents the yield limiting step with an average yield not exceeding 30%. 2) The Mitsunobu reaction is not involved in the new synthetic scheme avoiding the use of time and solvent consuming column chromatography. All synthesized triazinediones were preliminary pharmacologically screened in vivo for their ability to reduce the Bv8-induced thermal hyperalgesia. In this assay all compounds displayed EC50 values in the picomolar-subpicomolar range, some triazinediones containing a 4-halogen substituted benzyl group in position 5 showed the best activity. The analogues containing a 4-fluorine atom (PC-7) and a 4-bromobenzyl group (PC-25) resulted 10 times more potent than the reference PC-1 that bears a 4-ethylbenzyl group. While the 4-trifluoromethylbenzyl substituted analog (PC-27) was 100 times more potent as compared to PC1.
本文描述了一种基于三嗪二酮支架获得促动力蛋白受体拮抗剂的新型高效合成方法。在此过程中，总产率从13%提高到了约54%，主要有两个因素：1）不再使用N-（氯甲酰基）异氰酸酯，它是产率限制步骤，平均产率不超过30%。2）新的合成方案中不涉及Mitsunobu反应，避免了使用耗时且消耗溶剂的柱色谱法。所有合成的三嗪二酮均在体内进行了初步药理学筛选，以评估其降低Bv8诱导的热痛觉过敏的能力。在该试验中，所有化合物的EC50值均在皮摩尔至亚皮摩尔范围内，一些在5位含有4-卤素取代苄基的三嗪二酮表现出最佳活性。含有4-氟原子（PC-7）和4-溴苄基（PC-25）的类似物的效力比带有4-乙基苄基的参考PC-1强10倍。而4-三氟甲基苄基取代的类似物（PC-27）与PC1相比效力强100倍。
