2. Academic Validation
  3. 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

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

  • J Med Chem. 2026 May 14;69(9):11448-11470. doi: 10.1021/acs.jmedchem.6c00665.
Yuanbo Hu 1 2 3,  Yu Wang 1 2 3,  Wenhua Tan 1 2 3,  Congke Zhao 1 2 3,  Mengqi Li 1 2 3,  Sufang Xiang 1 2 3,  Xinru Liang 1 2 3,  Ruizhe Gao 4,  Bin Zeng 4,  Zhuo Chen 1 2 3,  Liqing Hu 4,  Qianbin Li 1 2 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China.
  • 2 Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Changsha 410013, Hunan, China.
  • 3 Hunan Key Laboratory of Organ Fibrosis, Changsha 410013, Hunan, China.
  • 4 Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Pharmaceutical Sciences, Hunan Normal University, Changsha 410013, Hunan, China.
PMID: 42018358 DOI: 10.1021/acs.jmedchem.6c00665
Abstract

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.

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