- Discovery of Novel Pyrazolo[3,4- b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension
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Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery.
- Hu, Liqing,Li, Lijun,Chang, Qi,Fu, Songsen,Qin, Jia,Chen, Zhuo,Li, Xiaohui,Liu, Qinglian,Hu, Gaoyun,Li, Qianbin
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p. 11215 - 11234
(2020/11/09)
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- ORGANIC PHOSPHORUS COMPOUNDS 76 SYNTHESIS AND PROPERTIES OF PHOSPHINOTHRICIN DERIVATIVES
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The synthesis, chemical and spectral properties of phosphinothricin analogues which either have other groups than methyl attached to phosphorus (30 to 40) or bear substituents on nitrogen (43 to 50) are described and the activity of some of these derivatives as glutamine synthetase inhibitors and contact herbicides is reported.
- Maier, Ludwig,Lea, Peter J.
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