Identification of Novel Imidazo[1,2-b]pyridazine Derivatives as Selective ROCK2 Inhibitors for the Treatment of Pulmonary Fibrosis.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-10-03 DOI:10.1021/acs.jmedchem.5c02233

Zhi Cao,Shuqi Wang,Jiajun Ma,Jiyu Du,Xiujian Wei,Lingfeng Yue,Jiahao Zhang,Zehui Tan,Xin Zhai

{"title":"Identification of Novel Imidazo[1,2-b]pyridazine Derivatives as Selective ROCK2 Inhibitors for the Treatment of Pulmonary Fibrosis.","authors":"Zhi Cao,Shuqi Wang,Jiajun Ma,Jiyu Du,Xiujian Wei,Lingfeng Yue,Jiahao Zhang,Zehui Tan,Xin Zhai","doi":"10.1021/acs.jmedchem.5c02233","DOIUrl":null,"url":null,"abstract":"Rho-associated coiled-coil containing protein kinase 2 (ROCK2) has been identified as a promising target for the treatment of pulmonary fibrosis (PF). In this study, a series of novel imidazo[1,2-b]pyridazine derivatives were designed as selective ROCK2 inhibitors. Through comprehensive investigation of SARs, compounds A25 and A26 exhibited superior ROCK2 inhibitory potency (IC50 = 7.0 and 8.7 nM, respectively) and excellent isoform selectivity (SI = 200/138). In bleomycin-induced PF mice models, administration of A25 and A26 resulted in a pronounced reduction of collagen deposition and a significant reversal of fibrotic progression. Mechanism study confirmed that A25 exerted antifibrotic effects via the TGF-β/Smad and ROCK2/STAT3 signaling pathways. Furthermore, A25 exhibited a favorable safety profile, showing low hERG channel inhibition and almost no pathological alterations in major organs. Overall, A25 was identified as a promising lead compound for the development of selective ROCK2 inhibitors for PF therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"45 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.5c02233","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Rho-associated coiled-coil containing protein kinase 2 (ROCK2) has been identified as a promising target for the treatment of pulmonary fibrosis (PF). In this study, a series of novel imidazo[1,2-b]pyridazine derivatives were designed as selective ROCK2 inhibitors. Through comprehensive investigation of SARs, compounds A25 and A26 exhibited superior ROCK2 inhibitory potency (IC50 = 7.0 and 8.7 nM, respectively) and excellent isoform selectivity (SI = 200/138). In bleomycin-induced PF mice models, administration of A25 and A26 resulted in a pronounced reduction of collagen deposition and a significant reversal of fibrotic progression. Mechanism study confirmed that A25 exerted antifibrotic effects via the TGF-β/Smad and ROCK2/STAT3 signaling pathways. Furthermore, A25 exhibited a favorable safety profile, showing low hERG channel inhibition and almost no pathological alterations in major organs. Overall, A25 was identified as a promising lead compound for the development of selective ROCK2 inhibitors for PF therapy.

查看原文本刊更多论文

新型咪唑[1,2-b]吡嗪衍生物作为选择性ROCK2抑制剂治疗肺纤维化的鉴定

rho相关的含卷曲卷曲蛋白激酶2 （ROCK2）已被确定为治疗肺纤维化（PF）的有希望的靶点。本研究设计了一系列新型咪唑[1,2-b]吡嗪衍生物作为选择性ROCK2抑制剂。综合研究发现，化合物A25和A26具有较强的ROCK2抑制力（IC50分别为7.0 nM和8.7 nM）和较好的同工异构体选择性（SI = 200/138）。在博莱霉素诱导的PF小鼠模型中，给药A25和A26导致胶原沉积明显减少，纤维化进展明显逆转。机制研究证实A25通过TGF-β/Smad和ROCK2/STAT3信号通路发挥抗纤维化作用。此外，A25表现出良好的安全性，在主要器官中表现出较低的hERG通道抑制和几乎没有病理改变。总的来说，A25被认为是开发用于PF治疗的选择性ROCK2抑制剂的有希望的先导化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.