| Autor: |
Lucas SCC, Atkinson SJ, Chung CW, Davis R, Gordon L, Grandi P; IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany., Gray JJR, Grimes T, Phillipou A, Preston AG, Prinjha RK, Rioja I, Taylor S, Tomkinson NCO; WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 259 Cathedral Street, Glasgow G1 1XL, U.K., Wall I, Watson RJ, Woolven J, Demont EH |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2021 Aug 12; Vol. 64 (15), pp. 10711-10741. Date of Electronic Publication: 2021 Jul 14. |
| DOI: |
10.1021/acs.jmedchem.1c00344 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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