EGT-022

6-(3-Methyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione referred to as EG22 (8a), is an open-chain 3-alkyl-1,2,3-triazene termed “combi-molecule” designed to inhibit poly(adenosine diphosphate ribose) polymerase (PARP) and damage DNA. To delay its hydrolysis, acetylation of N3 was required. Being a monoalkyl-1,2,3-triazene, EG22 could assume two tautomers in solution or lose nitrogen during the reaction, thereby leading to several acetylated compounds. Instead, one compound was observed and to unequivocally assign its structure, we introduced isotopically labeled reagents in its preparation, with the purpose of incorporating 15N at N2 and 13C in the 3-methyl group. The results showed that the 1,2,3-triazene moiety remained intact, as confirmed by 15N-NMR, coupling patterns between the 15N-labeled N2 and the 13C-labeled methyl group. Furthermore, we undertook heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond correlation (HMBC) experiments that permitted the detection and assignment of all four nitrogens in 6-(3-acetyl-3-methyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione, referred to as ZSM02 (9a), whose structure was further confirmed by X-ray crystallography. The structure showed a remarkable coplanarity between the N-acetyltriazene and the naphtalimide moiety. Thus, we unequivocally assigned 9a as the product of the reaction and compared its growth inhibitory activity with that of its precursor, EG22. ZSM02 exhibited identical growth inhibitory profile as EG22, suggesting that it may be a prodrug of EG22.

Background and objectives: EG-Mirotin (active ingredient EGT022) targets nonproliferative diabetic retinopathy (NPDR), the early stage of retinopathy. EG-Mirotin reverses capillary damage before NPDR progresses to an irreversible stage. EG-Mirotin safety and efficacy were investigated in patients with type 1 or type 2 diabetes mellitus and moderate to severe NPDR. Methods: In this open-label, single-arm, single-center, exploratory phase II study, 10 patients (20 eyes) received EG-Mirotin once a day (3 mg/1.5 mL sterile saline) for 5 days and were evaluated for ischemic index changes and safety. End of study was approximately 8 ± 1 weeks (57 ± 7 days) after the first drug administration. Results: EG-Mirotin injections were well tolerated, with no dose-limiting adverse events, serious adverse events, or deaths. Four treatment-emergent adverse events (TEAEs) unrelated to the investigational drug were observed in 2 out of 10 participants (20%) who had received the investigational drug. The overall average percent change in ischemic index at each evaluation point compared with baseline was statistically significant (Greenhouse–Geisser F = 9.456, p = 0.004 for the main effect of time), and a larger change was observed when the baseline ischemic index value was high (Greenhouse–Geisser F = 10.946, p = 0.002 for time × group interaction). Conclusions: The EG-Mirotin regimen established in this study was shown to be feasible and safe and was associated with a trend toward potential improvement in diabetes-induced ischemia and retinal capillary leakage.