Design and Optimization of LOXL2 and sGC Dual-Target Regulators Targeting Extracellular Matrix Dysregulation and Vasodilation for the Treatment of Pulmonary Arterial Hypertension

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.