Substituted 1-methyl-4-phenylpyrrolidin-2-ones - Fragment-based design of N-methylpyrrolidone-derived bromodomain inhibitors

被引：7

作者：

Hilton-Proctor, J. P. ^{[1
]}

Ilyichova, O. ^{[1
]}

Zheng, Z. ^{[1
]}

Jennings, I. G. ^{[1
]}

Johnstone, R. W. ^{[2
,3
]}

Shortt, J. ^{[4
,5
]}

Mountford, S. J. ^{[1
]}

Scanlon, M. J. ^{[1
]}

Thompson, P. E. ^{[1
]}

机构：

[1] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem, 381 Royal Parade, Parkville, Vic, Australia

[2] Peter MacCallum Canc Ctr, 305 Grattan St, Melbourne, Vic, Australia

[3] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic, Australia

[4] Monash Univ, Monash Hlth, Sch Clin Sci, Blood Canc Therapeut Lab, 246 Clayton Rd, Clayton, Vic, Australia

[5] Monash Hlth, Monash Haematol, 246 Clayton Rd, Clayton, Vic, Australia

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 191卷

关键词：

BRD4; Bromodomain; Epigenetics; K-ac; Fragment-based Drug Design; CHEMICAL PROBE; PHD FINGER; DISCOVERY; OPTIMIZATION; CONSTRUCTION; LIGANDS;

D O I：

10.1016/j.ejmech.2020.112120

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

N-Methylpyrrolidone is one of several chemotypes that have been described as a mimetic of acetyl-lysine in the development of bromodomain inhibitors. In this paper, we describe the synthesis of a 4-phenyl substituted analogue - 1-methyl-4-phenylpyrrolidin-2-one - and the use of aryl substitution reactions as a divergent route for derivatives. Ultimately, this has led to structurally complex, chiral compounds with progressively improved affinity as inhibitors of bromodomain-containing protein 4. (c) 2020 Elsevier Masson SAS. All rights reserved.

引用

页数：17

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