Design andOptimizationof LOXL2 and sGC Dual-TargetRegulators Targeting Extracellular Matrix Dysregulation and Vasodilationfor the Treatment of Pulmonary Arterial Hypertension

Abstract Current vasodilator therapies for pulmonary arterial hypertension (PAH) improve outcomes but remain limited in halting disease progression. Emerging evidence suggests that dual-acting agents targeting both vasodilation and vascular remodeling demonstrate superior efficacy. Leveraging the distinct roles of LOXL2 in vascular remodeling and sGC in vasodilation, we designed and synthesized a series of 4-(aminomethyl)-6-(trifluoromethyl)-2-(phenoxy)pyridine derivatives as dual LOXL2/sGC modulators via fragment fusion strategy. In vitro, compound 11k emerged as the most potent candidate, significantly suppressing pathological collagen cross-linking and malignant phenotypes while promoting vasodilation. In a hypoxia-induced PAH rat model, its esterified derivative 9k markedly alleviated vascular remodeling and reduced pulmonary artery pressure, showing efficacy comparable to the combination of riociguat and PAT-1251. Consequently, this study proposes a novel strategy for the development of bifunctional PAH drugs, with a focus on extracellular matrix dysfunction and vasoconstriction, and has identified a promising lead compound.