Citation: Yao Yangyang, Liu Xiaoyu, Yang Feilong, Yang Ying, Yuan Tianyi, Fang Lianhua, Du Guanhua, Jiao Xiaozhen, Xie Ping. Design, Synthesis and Biological Activity Evaluation of Novel Rho Kinase Inhibitors[J]. Chinese Journal of Organic Chemistry, ;2018, 38(4): 871-882. doi: 10.6023/cjoc201711007 shu

Design, Synthesis and Biological Activity Evaluation of Novel Rho Kinase Inhibitors

a.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050
b.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050

Corresponding author: Jiao Xiaozhen, jiaoxz@imm.ac.cn Xie Ping, xp@imm.ac.cn
Received Date: 3 November 2017
Revised Date: 24 November 2017
Available Online: 5 April 2017
Fund Project: Project supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (No. CIFMS 2016-I2M-3-009) and the Fundamental Research Funds for Chinese Academy of Medical Sciences (CAMS)/Peking Union Medical College (PUMC) (No. 2016ZX350024)the Fundamental Research Funds for Chinese Academy of Medical Sciences (CAMS)/Peking Union Medical College (PUMC) 2016ZX350024Project supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences CIFMS 2016-I2M-3-009

Figures(5)

Based on the structure of N-(1H-indazol-5-yl)-1-(4-methylbenzyl) pyrrolidine-3-carboxamide (I), which was previously obtained via a structure-based optimization of ROCK 1 inhibitor, sixteen novel 1-substituted-(1H-indazol-5-yl)tetrahydro pyrimidin-2(1H)-one derivatives were designed and synthesized via an active substructure combination strategy. The structures of the target compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. The bioassay data indicated that 1-(1H-indazol-5-yl)-3-(4-nitrophenyl) tetrahydropyrimidin-2(1H)-one (8a) and 4-(3-(1H-indazol-5-yl)-2-oxo tetrahydropyrimidin-1(2H)-yl)benzonitrile (8b) had good activities against ROCK I. The IC₅₀ values for 8a and 8b were 6.01 and 9.46 μmol·L^-1, respectively. Moreover, ex vivo studies demonstrated that 8a and 8b exhibited vasorelaxant activity in rat basilar artery ring. The EC₅₀ values for 8a and 8b were 15.92 and 20.61 μmol·L^-1, respectively.
- Rho-associated kinase,
- cardio-cerebrovascular disease,
- tetrahydro pyrimidin-2(1H)-one derivative,
- inhibitor
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