National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences and Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Bioorg Chem. 2022 Jul;124:105831. doi: 10.1016/j.bioorg.2022.105831. Epub 2022 Apr 25.
Bardoxolone methyl (CDDO-Me) has exhibited positive therapeutic effects in clinical trials for diabetic nephropathy (DN), but serious safety risks in the heart exist because of the potential off-target response resulting from the highly active part of CDDO-Me. Herein, we reported a novel strategy to prepare Cathepsin B (CTSB) cleavable and improved water-soluble prodrugs of CDDO-Me. CTSB linkers connection to the highly active α-cyano-α, β-unsaturated ketone (CUK) part of CDDO-Me with the incorporation of polyethylene glycol (PEG) moieties, provided a series of prodrugs of CDDO-Me without CUK part exposure. Theoretically, these prodrugs shielding CUK part can be stably circulated and finally cleaved by CTSB in lysosomes to release CDDO-Me. In this paper, preliminary curative effects and safety of all prodrugs were determined. Wherein, prodrug 20 displayed relatively better activities than other prodrugs in inhibiting the release of NO from RAW264.7 cells, activating Keap1-Nrf2-ARE signaling pathway and inhibiting NF-κB signaling pathway, which were comparable to CDDO-Me. More importantly, prodrug 20 showed relatively lower human ether-a-go-go-related gene (hERG) inhibitory activity compared with CDDO-Me, which demonstrated prodrug 20 might be safer than CDDO-Me. In conclusion, the novel strategy of shielding CUK part with CTSB linkers provided a new idea for solving the limitations of CDDO-Me in clinical application.
Bardoxolone 甲基（CDDO-Me）在糖尿病肾病（DN）的临床试验中表现出了积极的治疗效果，但由于 CDDO-Me 的高活性部分可能导致非靶向反应，因此在心脏方面存在严重的安全风险。在此，我们报道了一种制备组织蛋白酶 B（CTSB）可切割和改善水溶性 CDDO-Me 前药的新策略。CTSB 接头与 CDDO-Me 的高活性α-氰基-α，β-不饱和酮（CUK）部分连接，并结合聚乙二醇（PEG）部分，提供了一系列没有 CUK 部分暴露的 CDDO-Me 前药。从理论上讲，这些前药可以稳定地循环，并最终在溶酶体中被 CTSB 切割，释放出 CDDO-Me。本文初步确定了所有前药的疗效和安全性。其中，前药 20 在抑制 RAW264.7 细胞中 NO 的释放、激活 Keap1-Nrf2-ARE 信号通路和抑制 NF-κB 信号通路方面的活性均优于其他前药，与 CDDO-Me 相当。更重要的是，与 CDDO-Me 相比，前药 20 对人 ether-a-go-go-related gene（hERG）的抑制活性相对较低，这表明前药 20 可能比 CDDO-Me 更安全。总之，用 CTSB 接头屏蔽 CUK 部分的新策略为解决 CDDO-Me 在临床应用中的局限性提供了新的思路。
