ROCK inhibitor: Focus on recent updates

• Published in: Chinese chemical letters Vol. 34; no. 12; pp. 108336 - 125
• Main Authors: You, Yaodong, Zhu, Kun, Wang, Jie, Liang, Qi, Li, Wen, Wang, Lin, Guo, Baojun, Zhou, Jing, Feng, Xuanlin, Shi, Jianyou
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.12.2023; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province,Chengdu 610072,China%Hospital of Chengdu University of Traditional Chinese Medicine,Chengdu 610072,China%Guizhou University of Traditional Chinese Medicine,Guiyang 550002,China%College of Medicine,Southwest Jiaotong Unive,Chengdu 610031,China%College of Food and Bioengineering,Xihua University,Chengdu 610039,China%Department of Emergency Intensive Care Unit,Sichuan Academy of Medical Sciences & Sichuan Province People's Hospital,Chengdu 610072,China%Department of Pharmacy,Personalized Drug Therapy Key Laboratory of Sichuan Province,Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital,School of Medicine,University of Electronic Science and Technology,Chengdu 610072,China; Hospital of Chengdu University of Traditional Chinese Medicine,Chengdu 610072,China
• Subjects: Pharmacological activity; ROCK inhibitor; ROCK signaling pathway; ROCK-I; ROCK-II; Structure–activity relationship; ROCK-II; ROCK inhibitor; Pharmacological activity; ROCK signaling pathway; Structure–activity relationship; ROCK-I; ROCK-; Structure-activity relationship
• ISSN: 1001-8417; 1878-5964
• DOI: 10.1016/j.cclet.2023.108336

Rho-associated coiled-coil-containing protein kinase (ROCK) belongs to the serine-threonine family, and ROCK is involved in a variety of biological processes including cell migration, adhesion, proliferation and differentiation through phosphorylation of different downstream substrates. The aberrant activation of ROCK is associated with the pathological conditions in different systems including various diseases, including cancer, neurological diseases, inflammation, cardiovascular diseases and glaucoma. Therefore, the ROCK inhibitors have potential applicability for treating the aforementioned diseases. Four small molecule ROCK inhibitors have been approved for clinical use: fasudil, ripasudil, netarsudil and belumosudil. In recent years, more small molecule ROCK inhibitors have been identified. This paper reviews the ROCK inhibitors reported in past seven years. We mainly focused on the summarization of the structure–activity relationships, inhibitory efficacy, pharmacological mechanisms and the relevant clinical studies of the reported ROCK inhibitors. Besides the small molecular inhibitors, the peptides and biological extracts which exhibit ROCK inhibitory effects are also included. We also provide suggestions for the future development of the potent ROCK inhibitors. Rho-associated coiled-coil-containing protein kinase (ROCK) proteins are involved in many biological and physiological cellular functions and activities closely related to many diseases. This paper summarized more than 60 ROCK inhibitors with different chemical families, including isoquinoline, pyridine, indazole, pyrimidine, pyrroloxypyridine, pyrazole, benzothiophene, benzimidazole, naphthalene, purine, boron and other small molecule inhibitors. In addition, peptides as ROCK inhibitors were also reviewed in this paper. [Display omitted]