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

doi:10.6023/cjoc201711007

Chin. J. Org. Chem. ›› 2018, Vol. 38 ›› Issue (4): 871-882.DOI: 10.6023/cjoc201711007 Previous Articles Next Articles

Articles

新型Rho激酶抑制剂的设计、合成及生物活性评价

姚阳阳^a, 刘晓宇^a, 杨飞龙^a, 杨颖^a, 袁天翊^b, 方莲花^b, 杜冠华^b, 焦晓臻^a, 谢平^a

a 中国医学科学院&北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室活性物质发现与适药化研究北京市重点实验室北京 100050;
b 中国医学科学院&北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室药物靶点研究与新药筛选北京市重点实验室北京 100050

收稿日期:2017-11-03 修回日期:2017-11-24 发布日期:2017-12-05
通讯作者: 焦晓臻, 谢平 E-mail:jiaoxz@imm.ac.cn;xp@imm.ac.cn
基金资助:
中国医学科学院医学与健康科技创新工程资助项目（No.2016-I2M-3-009）、中国医学科学院、北京协和医学院“中央级公益性科研院所基本科研业务费”（No.2016ZX350024）资助项目.

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

Yao Yangyang^a, Liu Xiaoyu^a, Yang Feilong^a, Yang Ying^a, Yuan Tianyi^b, Fang Lianhua^b, Du Guanhua^b, Jiao Xiaozhen^a, Xie Ping^a

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

Received:2017-11-03 Revised:2017-11-24 Published:2017-12-05
Contact: 10.6023/cjoc201711007 E-mail:jiaoxz@imm.ac.cn;xp@imm.ac.cn
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).

1. Design, Synthesis and Biological Activity Evaluation of Novel Rho Kinase Inhibitors.PDF(1007KB)

Abstract

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.

Key words: Rho-associated kinase, cardio-cerebrovascular disease, tetrahydro pyrimidin-2(1H)-one derivative, inhibitor

Cite this article

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]. Chin. J. Org. Chem., 2018, 38(4): 871-882.

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[1] Zhang, X. F.; Hu, D. Y.; Ding, R. J.; Wang, H. C.; Yan, L. X. Chin. J. Cardiol. 2012, 40, 179.
[2] Matozaki, T.; Nakanishi, H.; Takai, Y. Cell. Signalling 2000, 12, 515.
[3] Mueller, B. K.; Mack, H.; Teuseh, N. Nat. Rev. Drug Discovery 2005, 4, 387.
[4] Riento, K.; Ridley, A. J. Nat. Rev. Mol. Cell Biol. 2003, 4, 446.
[5] Nakagawa, O.; Fujisawa, K.; Ishizaki, T.; Saito, Y.; Nakao, K.; Narumiya, S. FEBS Lett. 1996, 392, 189.
[6] Wirth, A. Biochim. Biophys. Acta 2010, 1802, 1276.
[7] Barbara, E. R.; Nathalie, F. W.; Cameron, J. W.; Julie, H. C.; Gordon, R. C. Atherosclerosis 2005, 183, 1.
[8] Surma, M.; Wei, L.; Shi, J. J. Future Cardiol. 2011, 7, 657.
[9] Sauzeau, V.; Le, M. E.; Bertoqlio, J.; Scalbert, E.; Pacaud, P.; Loirand, G. Circ. Res. 2001, 88, 1102.
[10] Shin, H.; Salomone, S.; Ayata, C. Expert Opin. Ther. Targets 2008, 12, 1547.
[11] Hu, E.; Lee, D. Curr. Opin. Invest. Drugs 2003, 4, 1065.
[12] Nakahara, T.; Moriuchi, H.; Yunoki, M.; Sakamato, K. Y Eur. J. Pharmacol. 2000, 389, 103.
[13] Oka, M.; Fagan, K.; Jone, P.; McMutry, I. Br. J. Pharmacol. 2008, 155, 444.
[14] Ying, H.; Biroc, S. L.; Li, W.; Alicke, B.; Xuan, J. A. Mol. Cancer Ther. 2005, 5, 2158.
[15] Somlyo, C.; Phelps, C.; Dipiperro, M.; Eto, M.; Read, P.; Barrett, M.; Gibson, J. FASEB J. 2003, 17, 223.
[16] Feng, Y. B.; Cameron, M. D.; Frackowiak, B.; Evelyn, G.; Li L.; Claudia R.; Thomas, S.; Philip, L. Bioorg. Med. Chem. Lett. 2007, 17, 2355.
[17] Chen, Y. T.; Thomas, D. B.; Weiser, A.; Griffin, E.; Lin, L.; Ruiz, C.; Michael, D. C.; Stephan, S.; Derek, D.; Thomas, S.; LoGrasso, P.; Feng, Y. B. Bioorg. Med. Chem. Lett. 2008, 18, 6406.
[18] Sessions, E. H.; Yin, Y.; Thomas, D. B.; Weiser, A.; Griffin, E.; Pocas, J.; Cameron, M. D.; Ruiz, C.; Lin, L.; Schurer, S. C.; Schroter, T.; LoGrasso, P.; Feng, Y. B. Bioorg. Med. Chem. Lett. 2008, 18, 6390.
[19] Sessions, E. H.; Smolinski, M.; Wang, B.; Frackowiak, B.; Chowdhury, S.; Yin, Y.; Chen, Y. T.; Ruiz, C.; Lin, L.; Pocas, J.; Schroter, T.; Cameron, M. D.; LoGrasso, P.; Feng, Y. B.; Bannister, T. D. Bioorg. Med. Chem. Lett. 2010, 20, 1939.
[20] Yin, Y.; Lin, L.; Ruiz C.; Cameron, M. D.; Pocas, J.; Grant, W.; Schroter, T.; Chen, W.; Duckett, D.; Schurer, S.; LoGrasso, P.; Feng, Y. B. Bioorg. Med Chem. Lett. 2009, 19, 6686.
[21] Fang, X. G.; Chen, Y. T.; Sessions, E. H.; Chowdhury, S.; Vojkovsky, T.; Yin, Y.; Pocas, J. R.; Grant, W.; Schroter, T.; Lin, L.; Ruiz, C.; Cameron, M. D.; LoGrasso, P.; Feng, Y. B. Bioorg. Med. Chem. Lett. 2011, 21, 1844.
[22] Chowdhury, S.; Chen, Y. T.; Fang, X. G.; Grant, W.; Pocas, J.; Cameron, M. D.; Ruiz, C.; Lin, L.; Park, H.; Schroter, T.; Bannister, T. D.; Feng, Y. B. Bioorg. Med. Chem. Lett. 2013, 23, 1592.
[23] Takami, A.; Iijima, H.; Iwakubo, M.; Okada, Y. EP 1256574, 2001.
[24] Iwakubo, M.; Takami, A.; Okada, Y.; Kawata, T.; Tagami, Y.; Sato, M.; Sugiyama, T.; Fukushima, K.; Taya, S.; Amano, M.; Kaibuchi, K.; Iijima, H. Bioorg. Med. Chem. 2007, 15, 1022.
[25] Henderson, A. J.; Hadden, M.; Guo, C.; Douglas, N.; Decornez, H.; Hellberg, M. R.; Rusinko, A.; McLaughlin, M.; Sharif, N.; Drace, C.; Patril, R. Bioorg. Med. Chem. Lett. 2010, 20, 1137.
[26] Feng, Y. B.; Philip, V. L.; Olivier, D.; Li, R. S. J. Med. Chem. 2016, 59, 2269.
[27] Yao, Y. Y.; Li, R. Z.; Liu, X. Y.; Yang, F. L.; Yang, Y.; Li, X. Y.; Shi, X.; Yuan, T. Y.; Fang, L. H.; Du, G. H.; Jiao, X. Z.; Xie, P. Molecules 2017, 22, 1766.
[28] Li, R. S.; Martin, M. P.; Liu, Y.; Khan, S.; Cameron, M. D.; Grant, W.; Pocas, J.; Eid, N.; Park, H.; Schroter, T.; LoGrasso, P.; Feng, Y. B. J. Med. Chem. 2012, 55, 2474.
[29] Chen, J. Q.; Li, Q. Preparation and Synthesis of Modern Drugs, Chemical Industry Press, Beijing, 2011, p. 55(in Chinese). (陈仲强, 李泉, 现代药物的制备与合成, 化学工业出版社, 北京, 2011, p. 55.)
[30] Marco, B.; Astrid, E.; Michele, T.; Achille, U. R. Angew. Chem., Int. Ed. 2008, 47, 3238.
[31] Mathieu, G.; Olivier, B. Org. Lett. 2012, 14, 398.
[32] Bian, C. C.; Yan, R.; Yu, X. M. Tetrahedron 2014, 70, 2982.
[33] Bosanac, T.; Hickey, E. R.; Ginn, J.; Kashem, M.; Kerr, S., Kugler, S.; Li, X.; Olague, A.; Schlyer, S.; Young, E. R. Bioorg. Med. Chem. Lett. 2010, 20, 3746.

新型Rho激酶抑制剂的设计、合成及生物活性评价

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

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