Structurally Minimalized and Druglike TGase2 Inhibitors Based on 7‑Aminoquinoline-5,8-dione Scaffolds for the Treatment of Diabetic Retinopathy

Diabetic retinopathy is a disease that can cause vision loss leading to blindness in people with diabetes. Improved methods to treat and prevent vision loss in diabetic patients are in high demand owing to limited current treatment procedures. Herein, we report a new class of transglutaminase 2 (TGase2) inhibitors for the treatment of diabetic retinopathy based on 7-aminoquinoline-5,8-dione derivatives. 7-Amino-2-phenylquinoline-5,8-dione 11 and 7-amino-2-{4-[(1-methylpiperidin-4-yl)­oxy]­phenyl}­quinoline-5,8-dione 23 exhibited potent inhibitory activities against TGase2 in a fibrinogen array-based on-chip TGase2 activity assay and in an in situ assay in human retinal microvascular endothelial cells, with IC50 values of 5.88 and 1.12 μM in vitro, and 0.09 and 0.07 μM in situ, respectively. Pharmacokinetically favorable 7-amino-2-{4-[(1-isopropylpiperidin-4-yl)­oxy] phenyl}­quinoline-5,8-dione 22 inhibited vascular leakage in the retinas of streptozotocin-induced diabetic mice via oral administration. Results from the AL5 kinetic assay and a molecular docking study suggest that the inhibitors may bind to TGase2 remote from the active site.

糖尿病视网膜病变（Diabetic retinopathy）是一种可导致糖尿病患者视力受损甚至失明的疾病。由于当前治疗手段有限，临床上亟需开发可用于治疗和预防糖尿病患者视力丧失的新型疗法。本文报道了一类基于7-氨基喹啉-5,8-二酮衍生物的新型谷氨酰胺转移酶2（transglutaminase 2, TGase2）抑制剂，用于糖尿病视网膜病变的治疗。7-氨基-2-苯基喹啉-5,8-二酮（化合物11）与7-氨基-2-{4-[(1-甲基哌啶-4-基)氧基]苯基}喹啉-5,8-二酮（化合物23）在基于纤维蛋白原阵列的芯片TGase2活性检测体系，以及人视网膜微血管内皮细胞的原位检测体系中，均表现出对TGase2的强效抑制活性；二者的体外半最大抑制浓度（IC50）分别为5.88 μM与1.12 μM，原位半最大抑制浓度则分别为0.09 μM与0.07 μM。药代动力学特性优良的7-氨基-2-{4-[(1-异丙基哌啶-4-基)氧基]苯基}喹啉-5,8-二酮（化合物22）可通过口服给药方式，抑制链脲佐菌素（streptozotocin）诱导的糖尿病小鼠视网膜血管渗漏。AL5动力学检测与分子对接实验结果表明，该类抑制剂可结合于TGase2远离活性位点的区域。