Chinese Journal of Organic Chemistry >
Design, Synthesis and Biological Activity Evaluation of Novel Rho Kinase Inhibitors
Received date: 2017-11-03
Revised date: 2017-11-24
Online published: 2017-12-05
Supported by
Project supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (No. CIFMS 2016-I2M-3-009) and the Fun-damental Research Funds for Chinese Academy of Medical Sciences (CAMS)/Peking Union Medical College (PUMC) (No. 2016ZX350024).
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.
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
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