Discovery and Optimization of Hsp110 and sGC Dual-Target Regulators for the Treatment of Pulmonary Arterial Hypertension

Currently, bifunctional agents with vasodilation and
ameliorated
vascular remodeling effects provide more advantages for the treatment
of pulmonary arterial hypertension (PAH). In this study, we first
screened the hit 1 with heat shock protein 110 (Hsp110)
inhibition effect from our in-house compound library with soluble
guanylate cyclase (sGC) activity. Subsequently, a series of novel
bisamide derivatives were designed and synthesized as Hsp110/sGC dual-target
regulators based on hit 1. Among them, 17i exhibited optimal Hsp110 and sGC molecular activities as well as
remarkable cell malignant phenotypes inhibitory and vasodilatory effects in vitro. Moreover, compared to riociguat, 17i showed superior efficacy in attenuating pulmonary vascular remodeling
and right ventricular hypertrophy via Hsp110 suppression in hypoxia-induced
PAH rat models (i.g.). Notably, our study successfully demonstrated
that the simultaneous regulation of Hsp110 and sGC dual targets was
a novel and feasible strategy for PAH therapy, providing a promising
lead compound for anti-PAH drug discovery.