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

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 re...

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Veröffentlicht in:Journal of medicinal chemistry 2020-10, Vol.63 (19), p.11215-11234
Hauptverfasser: Hu, Liqing, Li, Lijun, Chang, Qi, Fu, Songsen, Qin, Jia, Chen, Zhuo, Li, Xiaohui, Liu, Qinglian, Hu, Gaoyun, Li, Qianbin
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container_end_page 11234
container_issue 19
container_start_page 11215
container_title Journal of medicinal chemistry
container_volume 63
creator Hu, Liqing
Li, Lijun
Chang, Qi
Fu, Songsen
Qin, Jia
Chen, Zhuo
Li, Xiaohui
Liu, Qinglian
Hu, Gaoyun
Li, Qianbin
description 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.
doi_str_mv 10.1021/acs.jmedchem.0c01132
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subjects Adenylate Kinase - antagonists & inhibitors
Adenylate Kinase - metabolism
Animals
Cell Line
Drug Design
Humans
Hypertension, Pulmonary - drug therapy
Pyrazoles - chemistry
Pyrazoles - pharmacology
Pyridines - chemistry
Pyridines - pharmacology
Rats
Structure-Activity Relationship
Vascular Remodeling - drug effects
Vasodilation - drug effects
title 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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