Discovery of 2-((2-methylbenzyl)thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile as a novel and effective bromodomain and extra-terminal (BET) inhibitor for the treatment of sepsis

被引：9

作者：

Chen, Xuetao ^{[1
,2
,3
]}

Meng, Fanying ^{[1
,2
,3
]}

Zhang, Jingtian ^{[1
,2
,3
]}

Zhang, Zijian ^{[1
,2
,3
]}

Ye, Xuan ^{[2
,3
]}

Zhang, Weikun ^{[1
,2
,3
]}

Tong, Yuanyuan ^{[1
,2
,3
]}

Ji, Xinrui ^{[1
,2
,3
]}

Xu, Rujun ^{[1
,2
,3
]}

Xu, Xiao-Li ^{[1
,2
,3
]}

You, Qi-Dong ^{[1
,2
,3
]}

Jiang, Zheng-Yu ^{[1
,2
,3
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China

[3] China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 210009, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 238卷

基金：

中国国家自然科学基金;

关键词：

Sepsis; BRD4; inhibitor; Bromodomain; BET; SELECTIVE-INHIBITION; TARGETING BRD4; DRUG DISCOVERY; POTENT; INFLAMMATION; DESIGN; DERIVATIVES; PATHWAY; ASSAY;

D O I：

10.1016/j.ejmech.2022.114423

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Sepsis has long been a major health problem worldwide. It threatens the lives of hospitalized patients and has been one of the leading causes of death in hospitalized patients over the past decades. BRD4 has been regarded as a potential target for sepsis therapy, for its critical role in the transcriptional expression of NF-kappa B pathway-dependent inflammatory factors. In this study, compound 1 was obtained through virtual screening, and candidate compound 27 was obtained through several rounds of iterative SAR analysis. 27 decreased LPS-induced NO production and expression of the pro-inflammatory factors IL-6, IL-1 beta and TNF-alpha. In vivo, 27 effectively protected mice from LPS-induced sepsis, increased survival rate and decreased the level of pro-inflammatory factors in serum. Collectively, we reported here 27, a BRD4 inhibitor with a new scaffold, as a potential candidate for the treatment of sepsis.

引用

页数：15

共 79 条

[61] Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development [J].

Tang, Pan ;

Zhang, Jifa ;

Liu, Jie ;

Chiang, Cheng-Ming ;

Ouyang, Liang .

JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (05) :2419-2435

[62] Selective Antagonists of the Bronchiolar Epithelial NF-κB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation [J].

Tian, Bing ;

Liu, Zhiqing ;

Yang, Jun ;

Sun, Hong ;

Zhao, Yingxin ;

Wakamiya, Maki ;

Chen, Haiying ;

Rytting, Erik ;

Zhou, Jia ;

Brasier, Allan R. .

CELL REPORTS, 2018, 23 (04) :1138-1151

[63] The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus [J].

Vazquez, Ramiro ;

Riveiro, Maria E. ;

Astorgues-Xerri, Lucile ;

Odore, Elodie ;

Rezai, Keyvan ;

Erba, Eugenio ;

Panini, Nicolo ;

Rinaldi, Andrea ;

Kwee, Ivo ;

Beltrame, Luca ;

Bekradda, Mohamed ;

Cvitkovic, Esteban ;

Bertoni, Francesco ;

Frapolli, Roberta ;

D'Incalci, Maurizio .

ONCOTARGET, 2017, 8 (05) :7598-7613

[64] GSK789: A Selective Inhibitor of the First Bromodomains (BD1) of the Bromo and Extra Terminal Domain (BET) Proteins [J].

Watson, Robert J. ;

Bamborough, Paul ;

Barnett, Heather ;

Chung, Chun-wa ;

Davis, Rob ;

Gordon, Laurie ;

Grandi, Paola ;

Petretich, Massimo ;

Phillipou, Alex ;

Prinjha, Rab K. ;

Rioja, Inmaculada ;

Soden, Peter ;

Werner, Thilo ;

Demont, Emmanuel H. .

JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (17) :9045-9069

[65] BRD4 Inhibition Protects Against Myocardial Ischemia/Reperfusion Injury by Suppressing Inflammation and Oxidative Stress Through the PI3K/AKT Signaling Pathway [J].

Wei, Hongwei ;

Xue, Qingjian ;

Sun, Lei ;

Lv, Jie .

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 2021, 78 (06) :839-846

[66] Structure-Based Design of a Bromodomain and Extraterminal Domain (BET) Inhibitor Selective for the N-Terminal Bromodomains That Retains an Anti-inflammatory and Antiproliferative Phenotype [J].

Wellaway, Christopher R. ;

Bamborough, Paul ;

Bernard, Sharon G. ;

Chung, Chun-wa ;

Craggs, Peter D. ;

Cutler, Leanne ;

Demont, Emmanuel H. ;

Evans, John P. ;

Gordon, Laurie ;

Karamshi, Bhumika ;

Lewis, Antonia J. ;

Lindon, Matthew J. ;

Mitchell, Darren J. ;

Rioja, Inmaculada ;

Soden, Peter E. ;

Taylor, Simon ;

Watson, Robert J. ;

Willis, Rob ;

Woolven, James M. ;

Wyspianska, Beata S. ;

Kerr, William J. ;

Prinjha, Rab K. .

JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (17) :9020-9044

[67] Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11β-hydroxydehydrogenase 1 (11β-HSD1) [J].

Wu, Shung C. ;

Yoon, David ;

Chin, Janice ;

van Kirk, Katy ;

Seethala, Ramakrishna ;

Golla, Rajasree ;

He, Bin ;

Harrity, Thomas ;

Kunselman, Lori K. ;

Morgan, Nathan N. ;

Ponticiello, Randolph P. ;

Taylor, Joseph R. ;

Zebo, Rachel ;

Harper, Timothy W. ;

Li, Wenying ;

Wang, Mengmeng ;

Zhang, Lisa ;

Sleczka, Bogdan G. ;

Nayeem, Akbar ;

Sheriff, Steven ;

Camac, Daniel M. ;

Morin, Paul E. ;

Everlof, John G. ;

Li, Yi-Xin ;

Ferraro, Cheryl A. ;

Kieltyka, Kasia ;

Shou, Wilson ;

Vath, Marianne B. ;

Zvyaga, Tatyana A. ;

Gordon, David A. ;

Robl, Jeffrey A. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (22) :6693-6698

[68] Bromodomain Containing Protein 4 (BRD4) Regulates Expression of its Interacting Coactivators in the Innate Response to Respiratory Syncytial Virus [J].

Xu, Xiaofang ;

Mann, Morgan ;

Qiao, Dianhua ;

Li, Yi ;

Zhou, Jia ;

Brasier, Allan R. .

FRONTIERS IN MOLECULAR BIOSCIENCES, 2021, 8

[69] NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds [J].

Yu, Jun-lan ;

Chen, Tian-tian ;

Zhou, Chen ;

Lian, Fu-lin ;

Tang, Xu-long ;

Wen, Yi ;

Shen, Jing-kang ;

Xu, Ye-chun ;

Xiong, Bing ;

Zhang, Nai-xia .

ACTA PHARMACOLOGICA SINICA, 2016, 37 (07) :984-993

[70] Sepsis in Internal Medicine wards: current knowledge, uncertainties and new approaches for management optimization [J].

Zaccone, Vincenzo ;

Tosoni, Alberto ;

Passaro, Giovanna ;

Vallone, Carla Vincenza ;

Impagnatiello, Michele ;

Li Puma, Domenica Donatella ;

De Cosmo, Salvatore ;

Landolfi, Raffaele ;

Mirijello, Antonio .

ANNALS OF MEDICINE, 2017, 49 (07) :582-592

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