Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors

Simon C. C. Lucas; Stephen J Atkinson; Chun-Wa Chung; Rob Davis; Laurie Gordon; Paola Grandi; James J R Gray; Thomas Grimes; Alexander Phillipou; Alex G Preston; Rab K Prinjha; Inmaculada Rioja; Simon Taylor; Nicholas C. O. Tomkinson; Ian Wall; Robert J Watson; James Woolven; Emmanuel H Demont

doi:10.1021/acs.jmedchem.1c00344

Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors

Simon C. C. Lucas, Stephen J Atkinson, Chun-Wa Chung, Rob Davis, Laurie Gordon, Paola Grandi, James J R Gray, Thomas Grimes, Alexander Phillipou, Alex G Preston, Rab K Prinjha, Inmaculada Rioja, Simon Taylor, Nicholas C. O. Tomkinson, Ian Wall, Robert J Watson, James Woolven, Emmanuel H Demont

Pure And Applied Chemistry

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Abstract

Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.

Original language	English
Pages (from-to)	10711-10741
Number of pages	31
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	15
Early online date	14 Jul 2021
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00344
Publication status	Published - 12 Aug 2021

Keywords

amides
rodent models
bromo and extra-terminal domain (BET)
bromodomains
pan-BET inhibitors
rat
dog
pharmacokinetics

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10.1021/acs.jmedchem.1c00344

Lucas-etal-JMC-2021-Optimization-of-a-series-of-2-3-dihydrobenzofurans-as-highly-potent-second-bromodomainAccepted author manuscript, 1.74 MB

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Lucas, S. C. C., Atkinson, S. J., Chung, C.-W., Davis, R., Gordon, L., Grandi, P., Gray, J. J. R., Grimes, T., Phillipou, A., Preston, A. G., Prinjha, R. K., Rioja, I., Taylor, S., Tomkinson, N. C. O., Wall, I., Watson, R. J., Woolven, J., & Demont, E. H. (2021). Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors. Journal of Medicinal Chemistry, 64(15), 10711-10741. https://doi.org/10.1021/acs.jmedchem.1c00344

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title = "Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors",

abstract = "Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.",

keywords = "amides, rodent models, bromo and extra-terminal domain (BET), bromodomains, pan-BET inhibitors, rat, dog, pharmacokinetics",

author = "Lucas, {Simon C. C.} and Atkinson, {Stephen J} and Chun-Wa Chung and Rob Davis and Laurie Gordon and Paola Grandi and Gray, {James J R} and Thomas Grimes and Alexander Phillipou and Preston, {Alex G} and Prinjha, {Rab K} and Inmaculada Rioja and Simon Taylor and Tomkinson, {Nicholas C. O.} and Ian Wall and Watson, {Robert J} and James Woolven and Demont, {Emmanuel H}",

year = "2021",

month = aug,

day = "12",

doi = "10.1021/acs.jmedchem.1c00344",

language = "English",

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Lucas, SCC, Atkinson, SJ, Chung, C-W, Davis, R, Gordon, L, Grandi, P, Gray, JJR, Grimes, T, Phillipou, A, Preston, AG, Prinjha, RK, Rioja, I, Taylor, S, Tomkinson, NCO, Wall, I, Watson, RJ, Woolven, J & Demont, EH 2021, 'Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors', Journal of Medicinal Chemistry, vol. 64, no. 15, pp. 10711-10741. https://doi.org/10.1021/acs.jmedchem.1c00344

TY - JOUR

T1 - Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors

AU - Lucas, Simon C. C.

AU - Atkinson, Stephen J

AU - Chung, Chun-Wa

AU - Davis, Rob

AU - Gordon, Laurie

AU - Grandi, Paola

AU - Gray, James J R

AU - Grimes, Thomas

AU - Phillipou, Alexander

AU - Preston, Alex G

AU - Prinjha, Rab K

AU - Rioja, Inmaculada

AU - Taylor, Simon

AU - Tomkinson, Nicholas C. O.

AU - Wall, Ian

AU - Watson, Robert J

AU - Woolven, James

AU - Demont, Emmanuel H

PY - 2021/8/12

Y1 - 2021/8/12

N2 - Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.

AB - Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.

KW - amides

KW - rodent models

KW - bromo and extra-terminal domain (BET)

KW - bromodomains

KW - pan-BET inhibitors

KW - rat

KW - dog

KW - pharmacokinetics

U2 - 10.1021/acs.jmedchem.1c00344

DO - 10.1021/acs.jmedchem.1c00344

M3 - Article

C2 - 34260229

SN - 0022-2623

VL - 64

SP - 10711

EP - 10741

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

ER -

Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors

Abstract

Keywords

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