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Novel Derivative of Bardoxolone Methyl Improves Safety for the Treatment of Diabetic Nephropathy

Currently, no effective and safe medicines are available to treat diabetic nephropathy (DN). Bardoxolone methyl (CDDO-Me) has displayed promising anti-DN activity as well as serious side effects in clinical trials, probably because the highly reactive α-cyano-α,β-unsaturated ketone (CUK) in ring A of CDDO-Me can covalently bind to thiol functionalities in many biomacromolecules. In this study, we designed and synthesized a γ-glutamyl transpeptidase (GGT)-based and CUK-modified derivative of CDDO-Me (<b>2</b>) to address this issue. <b>2</b> can be specifically cleaved by GGT, which is highly expressed in the kidney, to liberate CDDO-Me in situ. It should be noted that <b>2</b> exhibited anti-DN efficacy comparable to that of CDDO-Me with much less toxicity in cells and <i>db</i>/<i>db</i> mice, suggesting that its safety is better than CDDO-Me. Our findings not only reveal the therapeutic potential of <b>2</b> but also provide a strategy to optimize other synthetic molecules or natural products bearing a pharmacophore like CUK to achieve safer pharmaceutical drugs

Identification of a Novel Hybridization from Isosorbide 5‑Mononitrate and Bardoxolone Methyl with Dual Activities of Pulmonary Vasodilation and Vascular Remodeling Inhibition on Pulmonary Arterial Hypertension Rats

Given the clinical therapeutic efficacy of oral-dosed bardoxolone methyl (<b>1</b>) and the selective vasodilatory effect caused by inhalation of nitric oxide (NO) on pulmonary arterial hypertension (PAH) patients, a new hybrid (CDDO-NO, <b>2</b>) from <b>1</b> and NO donor isosorbide 5-mononitrate (<b>3</b>) was designed and synthesized. This hybrid could liberate <b>1</b> and NO in the lungs of rats after trachea injection. Significantly, <b>2</b> lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure <b>(</b>RVSP), decreased right ventricular hypertrophy (RVH), and attenuated pulmonary artery medial thickness (PAMT) and vascular muscularization in monocrotaline (MCT)-induced PAH rats. Meanwhile, <b>2</b> inhibited overproliferation of perivascular cells and diminished macrophage infiltration and oxidative stress by inactivation of NOX4. In addition, <b>2</b> markedly reduced cardiac hypertrophy and fibrosis in the PAH rats. Overall, <b>2</b> exhibited potent dual activities of pulmonary vasodilation and vascular remodeling inhibition, suggesting that it may be a promising agent for PAH intervention