Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor,Journal of Medicinal Chemistry

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Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-08-10 , DOI: 10.1021/acs.jmedchem.1c00104
Xing Chen ₁ , Yaoyao Yan ₁ , Zhaoyan Zhang ₁ , Faming Zhang ₁ , Mingming Liu ₁ , Leran Du ₁ , Haixia Zhang ₁ , Xiaobao Shen ₁ , Dahai Zhao ₂ , Jing Bo Shi ₁ , Xinhua Liu ₁

Affiliation

Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent “non-peptidyl non-covalent cathepsin C inhibitor” was described with hit finding, structure optimization, and lead discovery. Starting with hit 14, structure-based optimization and structure–activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro. Also, compound 54 (with cathepsin C Enz IC₅₀ = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.

中文翻译：

新型非肽基非共价组织蛋白酶 C 抑制剂的发现及体内抗炎活性评价

组织蛋白酶 C (Cat C) 通过影响中性粒细胞丝氨酸蛋白酶 (NSP) 的激活参与炎症和免疫调节。因此，组织蛋白酶 C 是治疗 NSP 相关炎症性疾病的一个有吸引力的靶点。在此，从命中发现、结构优化和先导化合物发现三个方面描述了第一个强效“非肽基非共价组织蛋白酶C抑制剂”的完整发现过程。从hit 14开始，全面开展了基于结构的优化和构效关系研究，发现先导化合物54在体内和体外均是一种有效的类药组织蛋白酶C抑制剂。此外，化合物54 （与组织蛋白酶 C Enz IC ₅₀ = 57.4 nM）在慢性阻塞性肺病动物模型中表现出有效的抗炎活性。这些结果证实了非肽基和非共价衍生物可以用作有效的组织蛋白酶C抑制剂，并鼓励我们在此发现的基础上继续进一步的药物发现。

更新日期：2021-08-26

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