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

J. P. Hilton-Proctor; O. Ilyichova; Z. Zheng; I. G. Jennings; R. W. Johnstone; J. Shortt; S. J. Mountford; M. J. Scanlon; P. E. Thompson

doi:10.1016/j.ejmech.2020.112120

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

J. P. Hilton-Proctor, O. Ilyichova, Z. Zheng, I. G. Jennings, R. W. Johnstone, J. Shortt, S. J. Mountford, M. J. Scanlon, P. E. Thompson

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7 Citations (Scopus)

Abstract

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.

Original language	English
Article number	112120
Journal	European Journal of Medicinal Chemistry
Volume	191
DOIs	https://doi.org/10.1016/j.ejmech.2020.112120
Publication status	Published - 1 Apr 2020

Keywords

BRD4
Bromodomain
Epigenetics
Fragment-based Drug Design
K-ac

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Hilton-Proctor, J. P., Ilyichova, O., Zheng, Z., Jennings, I. G., Johnstone, R. W., Shortt, J., Mountford, S. J., Scanlon, M. J., & Thompson, P. E. (2020). Substituted 1-methyl-4-phenylpyrrolidin-2-ones – Fragment-based design of N-methylpyrrolidone-derived bromodomain inhibitors. European Journal of Medicinal Chemistry, 191, Article 112120. https://doi.org/10.1016/j.ejmech.2020.112120

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abstract = "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.",

keywords = "BRD4, Bromodomain, Epigenetics, Fragment-based Drug Design, K-ac",

author = "Hilton-Proctor, {J. P.} and O. Ilyichova and Z. Zheng and Jennings, {I. G.} and Johnstone, {R. W.} and J. Shortt and Mountford, {S. J.} and Scanlon, {M. J.} and Thompson, {P. E.}",

year = "2020",

month = apr,

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doi = "10.1016/j.ejmech.2020.112120",

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AU - Hilton-Proctor, J. P.

AU - Ilyichova, O.

AU - Zheng, Z.

AU - Jennings, I. G.

AU - Johnstone, R. W.

AU - Shortt, J.

AU - Mountford, S. J.

AU - Scanlon, M. J.

AU - Thompson, P. E.

PY - 2020/4/1

Y1 - 2020/4/1

N2 - 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.

AB - 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.

KW - BRD4

KW - Bromodomain

KW - Epigenetics

KW - Fragment-based Drug Design

KW - K-ac

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AN - SCOPUS:85080057839

SN - 0223-5234

VL - 191

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 112120

ER -

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

Abstract

Keywords

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