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Bioorg Med Chem Lett. 2012 Nov 1;22(21):6671-6. doi: 10.1016/j.bmcl.2012.08.102. Epub 2012 Sep 6.

Discovery of phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, an effective antithrombotic agent without associated bleeding and insulin resistance.

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  • 1Medicinal Chemistry, AstraZeneca R&D, CVGI iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.


Structure-based evolution of the original fragment leads resulted in the identification of 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, (S)-21, a potent, selective phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor with favourable in vivo antiplatelet effect. Despite its antiplatelet action, (S)-21 did not significantly increase bleeding time in dogs. Additionally, due to its enhanced selectivity over p110α, (S)-21 did not induce any insulin resistance in rats.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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