抑制血管內皮細胞生長因子作用的先導藥物最佳化和新穎藥物傳輸配方設計

Abstract

基於先前實驗的結果，我們發現 編號194的化合物對於VEGFR-3的抑制能力較編號1250的化合物為佳。因此先導藥物從#1250更改為#194，並且開始了各式各樣的評估實驗。然上述先導化合物均顯示低或難溶於水的性質，因此、持續修飾化合物結構或利用適當配方技術可以解決低溶解度相關問題。此外，治療腫瘤的小分子藥物可由適當的藥物傳輸及配方技術提高藥物功能。光田醫院吳世冠博士所做的新配方可增加 #194的水溶性至6 mg/mL，並且利用此新的配方進行藥物動力學和毒理實驗。 此外，郭明良教授和他的同僚目前也致力於#194新配方在生物活體上的腫瘤研究。 除了使用新配方來增加溶解度之外，我們也試著改變化合物的結構來提高抑制血管新生因子的活性和溶解度。藉由更改benzimidazole的取代基，我們已經合成一系列的#194衍生物，當benzimidazole的取代基為2-phenyl ethyl時所得到的抑制效果最佳 (#376)。 但是#376溶解度比#194差，我們可以利用其他取代基來增加溶解度及抑制活性。 我們已經設計了一系列的雜環取代基包含pyridinyl取代基 (可做成鹽類) 來提高抑制活性和溶解度性。 此外，我們也將benzimidazole部分更改為其他的雜環分子來提高#194的抑制效果。 同時我們也將繼續利用微波式組合化學合成新穎的化學分子庫並將這些分子送給郭教授篩選。化合物201， 355， 368和440是最近發現的新化合物，他們比194有更好的VEGFR-3抑制能力且這些化合物的核心結構與194不同。 最近，曾宇鳳博士利用了VEGFR-2的蛋白質結構及VEGFR-3蛋白質序列模擬出VEGFR-3的蛋白質結構，我們將之前篩選過的化合物整理後送給曾博士計算他們與VEGFR-3結合的情形，這些訊息及我們的經驗都是在未來開發更具活性的VEGFR-3抑制劑重要的依據。

Based on the results of previous efforts, we have found that the inhibition ability of compound #194 toward VEGFR-3 is much better than compound #1250. However, these compounds are poor water-soluble. As results, further developing these compounds into drug candidates was hampered. To resolve this problem, methods of structure modifications or formulation designs of drug candidate can be applied. The drug candidate was shifted from #1250 to #194 and various experiments were started to evaluated #194-acid form. Dr. Shih-Kuan Wu has made new formulations to increase the solubility to the level of 6 mg/ml and the pharmacokinetic and toxicity studies are continuously processing. Furthermore, Dr. Ming-Liang Kuo and his colleagues focus on the in vivo study on mice cancer mobility and growth with new formulation of 194-acid form. Besides using new formulation to increase the solubility, we also tried to design more focused compounds with higher potency and water solubility accordingly. We have synthesized a series of #194 derivatives by varying the substituent on benzimidazole and excellent results were obtained with 2-ethyl phenyl group on the benzimidazole (#376). The solubility of #376 was worse than #194, but it can be replaced the phenyl with other groups to satisfy with our demands. Such as pyridinyl group and a series of substituents for better potential and solubility were designed to be synthesized. Besides, we also tried to change the benzimidazole portion of #194 to other heterocyclic scaffolds to find out more potential inhibitors. Simultaneously, we will also continue to synthesize novel compound libraries and explored these compounds on screening platform established by Dr. Ming-Liang Kuo. Compounds #201, #355, #368 and #440 possess higher VEGFR-3 inhibition abilities than #194 and all these core structures were different from #194 which is patentable in the near future. Recently, Dr. Tseng has simulated the optimized protein structure of VEGFR-3 from VEGFR-2 and she will calculate the binding mode of VEGFR-3 with those compounds which have been identified with high biological activity. Based on this information of molecular modeling and our experiences, we will be guided to discover more potent compounds with good water solubility.