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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.

• The pathology of PAH is characterized by increased mPAP and elevated PVR on account of vasoconstriction and vascular remodeling. • Current medications primarily vasodilate with less consideration of vascular remodeling, leading to the clinical needs are still not met and PAH remains not curative. • The anti-vascular remodeling drugs failed to quickly reduce the patient's PAP in treating PAH clinically. • Emerging novel therapeutic approaches in PAH treatment with dual activities of vasodilation and vascular remodeling inhibition exert enormous advantages. Pulmonary arterial hypertension (PAH) is a rapidly progressing disease with limited therapeutic options. Studies have elucidated the multifactorial pathological characteristics of PAH, indicating the complexity and difficulty of PAH treatment. Currently available treatments focus primarily on vasodilation rather than on vascular remodeling, although several drugs have been developed for the latter. This paradigm for management leads to PAH remaining an incurable disease; thus, there is an urgent need to explore new strategies for coping with this devastating disease. In this review, we discuss current strategies and options for PAH therapy and emerging novel therapeutic approaches in PAH treatment. This viewpoint suggests a shift in PAH treatment strategy from mono-activity to dual effects on vasoconstriction and vascular remodeling. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a progressive and life-threatening disease with poor prognosis despite many advances in medical therapy over the past 20 years. Novel therapies which target on the underlying pathology of PH are still urgent to be met. TPN171H is a recently found new compound that exhibits potent pharmacological effects in PH via inhibiting phosphodiesterase type 5 (PDE-5). However, as one icariin derivative, the anti-inflammatory effects of TPN171H for treating PH are not clear. The present study was designed to investigate the therapeutical effect of TPN171H against inflammation in PH and reveal the underlying mechanism. Hypoxia and monocrotaline (MCT)-induced PH rat models were established, which were treated by oral administration of TPN171H (5, 25 mg/kg/d) or sildenafil (25 mg/kg/d). The right ventricle systolic pressure (RVSP), right ventricle hypertrophy index (RVHI) and vascular remodeling were measured. The results suggested that TPN171H significantly reduced RVSP and RVHI, and reversed pulmonary vascular remodeling in rats with both models. Furthermore, in in vivo and in vitro research, our data suggested that TPN171H remarkably suppressed cathepsin B-mediated NLRP3 inflammasome activation, which may contribute to its therapeutical function for PH. [Display omitted] • TPN171H can improve the abnormalities of RVSP, RVHI and pulmonary artery remodeling in PH rats induced by hypoxia and MCT. • TPN171H can inhibit the proliferation and migration of HPAECs induced by hypoxia and TNF-α. • TPN171H attenuates PH by inhibiting Cathepsin B/NLRP3/IL-1β signaling pathway both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disorder marked by vascular remodeling, which is linked to the malignant phenotypes of pulmonary vascular cells. The prevailing therapeutic approaches for PAH tend to neglect the potential role of vascular remodeling, leading to the clinical prognosis remains poor. Previously, we first demonstrated that heat shock protein (Hsp110) was significantly activated to boost Hsp110-STAT3 interaction, which resulted in abnormal proliferation and migration of human pulmonary arterial endothelial cells (HPAECs) under hypoxia. In the present study, we initially postulated the allosteric site of Hsp110, performed a virtual screening and biological evaluation studies to discover novel Hsp110-STAT3 interaction inhibitors. Here, we identified compound 29 (AN-329/43448068) as the effective inhibitor of HPAECs proliferation and the Hsp110-STAT3 association with good druggability. In vitro , 29 significantly impeded the chaperone function of Hsp110 and the malignant phenotypes of HPAECs. In vivo , 29 remarkably attenuated pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-induced PAH rats (i.g). Altogether, our data support the conclusion that it not only provides a novel lead compound but also presents a promising approach for subsequent inhibitor development targeting Hsp110-STAT3 interaction. [Display omitted] • The allosteric site of Hsp110 that may mediate the Hsp110-STAT3 interaction was first identified. • Allosteric site-based virtual screening combined with preliminary bioactivity evaluation led to the discovery of 29. • Compared to 2h , the novel skeleton compound 29 displays superior druggability. • In vitro , 29 significantly inhibited the malignant phenotypes of HPAECs via disrupting the Hsp110-STAT3 interaction. • In vivo , 29 remarkably attenuated pulmonary vascular remodeling in hypoxia-induced PAH rats. [ABSTRACT FROM AUTHOR]