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.

2023-10-26·Journal of medicinal chemistry1区 · 医学

Design, Synthesis, and Biological Evaluation of Novel Thioureidobenzamide (TBA) Derivatives as HBV Capsid Assembly Modulators.

1区 · 医学

Article

作者: Zhang, Xiaohui ; Wang, Yuanze ; Dou, Yutong ; Zhang, Jian ; Zhang, Lei ; Xue, Peng ; Xie, Yong ; Wang, Mei ; Hu, Huili ; Li, Chuanju ; Zhan, Peng ; Tao, Feiyan ; Liang, Minghui ; Wu, Zhuanchang ; Liu, Linyue ; Feng, Kairui ; Jia, Haiyong ; Chen, Yunfu

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, we designed and synthesized five series of benzamide derivatives based on a multisite-binding strategy at the tolerant region and diversity modification in the solvent-exposed region. Among them, thioureidobenzamide compound 17i exhibited significantly increased anti-HBV activity in HepAD38 (EC₅₀ = 0.012 μM) and HBV-infected HLCZ01 cells (EC₅₀ = 0.033 μM). Moreover, 17i displayed a better inhibitory effect on the assembly of HBV capsid protein compared with NVR 3-778 and a inhibitory effect similar to the clinical drug GLS4. In addition, 17i showed moderate metabolic stability in human microsomes, had excellent oral bioavailability in Sprague-Dawley (SD) rats, and inhibited HBV replication in the HBV carrier mice model, which could be considered as a promising candidate drug for further development.

2023-08-01·European Journal of Medicinal Chemistry

Discovery, optimization and biological evaluation of novel HBsAg production inhibitors

Article

作者: Zhang, Yang ; Lu, Dandan ; Xu, Hongjiang ; Wang, Xiaojin ; Chen, Shuo ; Jin, Hui ; Zhang, Yinsheng ; Ge, Xingfeng ; Zhang, Li ; Ao, Wangwei

A series of tetrahydropyridine (THP) derivatives I [R¹ = 6-fluoro-4-(propan-2-yl)pyridin-2-yl, 4-[(cyclopropylmethyl)amino]-6-fluoropyridin-2-yl, 6-fluoro-4-(3-fluoroazetidin-1-yl)pyridin-2-yl, etc.] and II [X = CH ,N; R² = dimethylamino, 3-fluoroazetidin-1-yl, methoxy, etc.] with a bridged ring were synthesized and evaluated for their inhibiting HBsAg production and HBV DNA activity.Among them, compound I [R¹ = 6-fluoro-4-(3-fluoroazetidin-1-yl)pyridin-2-yl (II)] was identified as potent HBsAg production inhibitor with excellent in vitro anti-HBV potency (HBV DNA EC₅₀ = 0.018μM, HBsAg EC₅₀ = 0.044μM) and low toxicity (CC₅₀ > 100μM).Moreover, compound (II) exhibited favorable in vitro/in vivo DMPK properties in mice.Compound (II) could also significantly reduce serum HBsAg and HBV DNA levels (1.08 and 1.04 log units, resp.) in HBV transgenic mice.

100 项与 17-i 相关的药物交易

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