Activity of the heme synthesis enzyme ferrochelatase (FECH) is implicated in multiple diseases. In particular, it is a mediator of neovascularization in the eye and thus an appealing therapeutic target for preventing blindness. However, no drug-like direct FECH inhibitors are known. Here, we set out to identify small-molecule inhibitors of FECH as potential therapeutic leads using a high-throughput screening approach to identify potent inhibitors of FECH activity. A structure-activity relationship study of a class of triazolopyrimidinone hits yielded drug-like FECH inhibitors. These compounds inhibit FECH in cells, bind the active site in cocrystal structures, and are antiangiogenic in multiple in vitro assays. One of these promising compounds was antiangiogenic in vivo in a mouse model of choroidal neovascularization. This foundational work may be the basis for new therapeutic agents to combat not only ocular neovascularization but also other diseases characterized by FECH activity.

血红素合成酶亚铁螯合酶 (FECH) 的活性与多种疾病有关。特别是，它是眼睛新生血管形成的介质，因此是预防失明的一个有吸引力的治疗靶点。然而，尚无已知的类似药物的直接 FECH 抑制剂。在这里，我们着手使用高通量筛选方法来鉴定 FECH 的小分子抑制剂作为潜在的治疗先导药物，以鉴定 FECH 活性的有效抑制剂。对一类三唑并嘧啶酮的构效关系研究产生了药物样 FECH 抑制剂。这些化合物抑制细胞中的 FECH，结合共晶结构中的活性位点，并且在多种体外测定中具有抗血管生成作用。这些有前途的化合物之一在脉络膜新生血管形成的小鼠模型中具有体内抗血管生成作用。这项基础工作可能成为新治疗药物的基础，不仅可以对抗眼部新生血管形成，还可以对抗其他以 FECH 活性为特征的疾病。