Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 4, Pages 1474-1482Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01153
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Funding
- National Natural Science Foundation of China [81673305, 81773573, 81473272]
- Jiangsu Province Funds for Distinguished Young Scientists [BK20160033]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Program for New Century Excellent Talents in University [NCET-13-1033]
- College Students Innovation Project for the R&D of Novel Drugs [J1030830]
- Jiangsu Shuang Chuang
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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.
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