7 research outputs found
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