Design and Optimization of LOXL2 and sGC Dual-Target Regulators Targeting Extracellular Matrix Dysregulation and Vasodilation for the Treatment of Pulmonary Arterial Hypertension #MMPMID41389019
Hu Y; Wang Y; Tan W; Zhao C; Li M; Xiang S; Liang X; Gao R; Zeng B; Chen Z; Hu L; Li Q
J Med Chem 2025[Dec]; ? (?): ? PMID41389019show ga
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.
J+Med+Chem 2025 ; ? (?): ?
