Key result
Compound 2 exhibited moderate vasodilation and higher proliferation/migration suppression than riociguat in vitro, and significantly decreased RVSP, PAMT, and RVH in hypoxia-induced PAH rat models.
Why the study?
Current pulmonary arterial hypertension therapies focus mainly on vascular relaxation rather than vascular remodeling, resulting in poor prognosis.
Does compound 2, a novel dual sGC stimulator and AMPK inhibitor, improve hemodynamics and vascular remodeling in hypoxia-induced PAH rat models?
Does compound 2, a novel dual sGC stimulator and AMPK inhibitor, improve hemodynamics and vascular remodeling in hypoxia-induced PAH rat models?
A novel pyrazolo[3,4-b] pyridine derivative demonstrates dual vasodilation and vascular remodeling inhibition, offering a promising lead for pulmonary arterial hypertension drug discovery.
Answers are grounded in this paper and cite their sources.
Should not change PAH practice; hypothesis-generating for dual sGC/AMPK inhibition and needs human trials.
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.
No takes yet. Share an insight, caveat, or question.
Hu et al. (2020) studied Pulmonary arterial hypertension. Compound 2 (novel pyrazolo[3,4-b] pyridine derivative) vs. Riociguat was evaluated on Vasodilation activity, proliferation and migration suppressive effects, right ventricular systolic pressure, pulmonary artery medial thickness, and right ventricular hypertrophy. Compound 2 exhibited moderate vasodilation and higher proliferation/migration suppression than riociguat in vitro, and significantly decreased RVSP, PAMT, and RVH in hypoxia-induced PAH rat models.
Synapse has enriched 10 related papers. Consider them for comparative context: