2. Academic Validation
  3. Discovery and Optimization of Hsp110 and sGC Dual-Target Regulators for the Treatment of Pulmonary Arterial Hypertension

Discovery and Optimization of Hsp110 and sGC Dual-Target Regulators for the Treatment of Pulmonary Arterial Hypertension

  • J Med Chem. 2024 Aug 8;67(15):13474-13490. doi: 10.1021/acs.jmedchem.4c01364.
Yuanbo Hu 1 2 3,  Congke Zhao 1 2 3,  Wenhua Tan 1 2 3,  Mengqi Li 1 2 3,  Yu Wang 1 2 3,  Ruizhe Gao 4,  Zhuo Chen 1 2 3,  Zhenming Jin 5,  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, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha 410013, Hunan, China.
  • 5 College of Biology, Hunan University, Changsha 410082, Hunan, China.
PMID: 39058542 DOI: 10.1021/acs.jmedchem.4c01364
Abstract

Currently, bifunctional agents with vasodilation and ameliorated vascular remodeling effects provide more advantages for the treatment of pulmonary arterial hypertension (PAH). In this study, we first screened the hit 1 with heat shock protein 110 (Hsp110) inhibition effect from our in-house compound library with soluble Guanylate Cyclase (sGC) activity. Subsequently, a series of novel bisamide derivatives were designed and synthesized as Hsp110/sGC dual-target regulators based on hit 1. Among them, 17i exhibited optimal Hsp110 and sGC molecular activities as well as remarkable cell malignant phenotypes inhibitory and vasodilatory effects in vitro. Moreover, compared to riociguat, 17i showed superior efficacy in attenuating pulmonary vascular remodeling and right ventricular hypertrophy via Hsp110 suppression in hypoxia-induced PAH rat models (i.g.). Notably, our study successfully demonstrated that the simultaneous regulation of Hsp110 and sGC dual targets was a novel and feasible strategy for PAH therapy, providing a promising lead compound for anti-PAH drug discovery.

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