- PROCESS FOR THE PREPARATION OF SUBSTITUTED PYRIMIDINES
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This invention relates to an improved process of making compounds of Formula (I) and synthetic intermediates thereof. (I) In particular, the invention relates to an improved process to prepare N-(2-aminophenyl)-4- ((pyrimidin-2-ylamino)methyl)benzamides which requires fewer steps, is efficient, can be used on an industrial scale, and results in a final product which is suitable for pharmaceutical use.
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- Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N-(2-aminophenyl)benzamide binding unit
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The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzamide 24a gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl) benzamides previously reported, an example of each ring system at 1 μM causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by 24a was observed, with respective IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.
- Marson, Charles M.,Matthews, Christopher J.,Yiannaki, Elena,Atkinson, Stephen J.,Soden, Peter E.,Shukla, Lena,Lamadema, Nermina,Thomas, N. Shaun B.
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p. 6156 - 6174
(2013/09/02)
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- Discovery of N-(2-Aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino) methyl]benzamide(MGCD0103), an orally active histone deacetylase inhibitor
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The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4- [(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21ciP/waf1 protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
- Zhou, Nancy,Moradei, Oscar,Raeppel, Stephane,Leit, Silvana,Frechette, Sylvie,Gaudette, Frederic,Paquin, Isabelle,Bernstein, Naomy,Bouchain, Giliane,Vaisburg, Arkadii,Jin, Zhiyun,Gillespie, Jeff,Wang, James,Fournel, Marielle,Yan, Pu T.,Trachy-Bourget, Marie-Claude,Kalita, Ann,Lu, Aihua,Rahil, Jubrail,MacLeod, A. Robert,Li, Zuomei,Besterman, Jeffrey M.,Delorme, Daniel
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scheme or table
p. 4072 - 4075
(2009/05/27)
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- Inhibitors of histone deacetylase
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The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
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- Inhibitors of histone deacetylase
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The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
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