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