Identification of Nitric Oxide-Donating Lenumlostat Derivatives with Dual Activities of Extracellular Matrix Dysregulation Inhibition and Pulmonary Vasodilation for the Treatment of Pulmonary Arterial Hypertension.

Based on two key pathological features of pulmonary arterial hypertension (PAH), elevated pulmonary artery pressure and vascular remodeling, two new series of nitric oxide (NO) donating lenumlostat derivatives were designed, synthesized, and biologically evaluated. The results indicated that compound LNO 9 exhibited LOXL2 inhibitory activity comparable to lenumlostat, remarkably suppressing hypoxia-induced collagen oxidation and aberrant collagen cross-linking. Furthermore, LNO 9 effectively released NO and increased 3',5'-cyclic guanosine monophosphate in HPASMCs, thereby exerting a potent vasodilation. In both hypoxia- and MCT-induced rat models of PAH, LNO 9 significantly improved right ventricular hypertrophy and pulmonary arterial medial wall thickness. Meanwhile, LNO 9 demonstrated superior efficacy in reducing right ventricular systolic pressure compared to lenumlostat. In short, the present study has demonstrated unequivocally that a therapeutic approach for PAH that combines NO donors for vasodilation with extracellular matrix inhibitors to suppress vascular remodeling represents a promising treatment.