Structurally\nMinimalized and Druglike TGase2 Inhibitors\nBased on 7‑Aminoquinoline-5,8-dione Scaffolds for the Treatment\nof Diabetic Retinopathy

Diabetic retinopathy is a disease that can cause vision\nloss leading\nto blindness in people with diabetes. Improved methods to treat and\nprevent vision loss in diabetic patients are in high demand owing\nto limited current treatment procedures. Herein, we report a new class\nof transglutaminase 2 (TGase2) inhibitors for the treatment of diabetic\nretinopathy based on 7-aminoquinoline-5,8-dione derivatives. 7-Amino-2-phenylquinoline-5,8-dione <b>11</b> and 7-amino-2-{4-[(1-methylpiperidin-4-yl)­oxy]­phenyl}­quinoline-5,8-dione <b>23</b> exhibited potent inhibitory activities against TGase2 in\na fibrinogen array-based on-chip TGase2 activity assay and in an in\nsitu assay in human retinal microvascular endothelial cells, with\nIC<sub>50</sub> values of 5.88 and 1.12 μM in vitro, and 0.09\nand 0.07 μM in situ, respectively. Pharmacokinetically favorable\n7-amino-2-{4-[(1-isopropylpiperidin-4-yl)­oxy] phenyl}­quinoline-5,8-dione <b>22</b> inhibited vascular leakage in the retinas of streptozotocin-induced\ndiabetic mice via oral administration. Results from the AL5 kinetic\nassay and a molecular docking study suggest that the inhibitors may\nbind to TGase2 remote from the active site.