以脯氨酸羟化酶抑制剂菲啰啉酮膦酸为基础的“前药”的设计、合成及抗肝纤维化作用的研究

肝纤维化是世界范围内亟待解决的重大健康问题，但迄今为止临床上尚缺乏有效逆转或阻止其进展的治疗药物。在慢性肝病-肝硬化-肝癌“三部曲”中，肝硬化状态一旦形成则无法逆转，然而其病理过程中必然经历的“肝纤维化阶段”的可逆转性已经被国内外学者认可和证实。肝纤维化的实质是胶原的过度合成和沉积，脯氨酸羟化酶是胶原合成过程中的关键酶，是公认的抗纤维化的有效靶点。本研究以前期工作发现的脯氨酸羟化酶抑制剂菲啰啉酮膦酸为原药，设计并合成多类膦酸前药，研究其对肝实质细胞和肝星状细胞的作用，发现其作用规律和差异，筛选出目标前药，开展体内肝器官靶向抗纤维化评价。本项目的成功将不仅获得有效的抗肝纤维化先导/候选化合物，而且对研究与开发肝器官靶向性前药具有指导作用。

Hepatic fibrosis has become a major health problem worldwide. Thus far, there is no effective therapeutics to reverse or block its progress. In the three stages of “chronic liver disease - liver cirrhosis - liver cancer”, fibrosis is the common pathological process. Recently, it has been recognized as reversible. Liver fibrosis is materially the process of excessive synthesis and deposition of collagen. Prolyl 4-hydroxylase (P4H) is a key enzyme in collagen synthesis and recognized as an effective target for anti-fibrosis treatment. In this application, we will design and synthesize several types of derivatives from a 1,10-phenanthrolinonephosphonic acid as “prodrugs” and evaluate both in vitro and in vivo anti-fibrosis activities. The prototype phosphonic acid is our previously discovered P4H inhibitor, the parent of a liver-targeted prodrug candidate currently in preclinical development for anti-fibrosis. The success of this project will not only result in lead/candidate compounds for liver fibrosis, but also provide useful information for discovery of liver-targeted drugs.