Abstract
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.
MeSH terms
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1-Phosphatidylinositol 4-Kinase / antagonists & inhibitors*
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Animals
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Bleeding Time
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Blood Platelets / drug effects*
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Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
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Dogs
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Drug Discovery*
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Fibrinolytic Agents / chemical synthesis*
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Fibrinolytic Agents / chemistry
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Fibrinolytic Agents / pharmacology*
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Inhibitory Concentration 50
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Insulin Resistance
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Molecular Structure
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Morpholines / chemical synthesis*
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Morpholines / chemistry
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Morpholines / pharmacology*
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Protein Isoforms / antagonists & inhibitors*
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Pyrimidinones / chemical synthesis*
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Pyrimidinones / chemistry
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Pyrimidinones / pharmacology*
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Rats
Substances
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4-(2-hydroxyethyl(1-naphthylmethyl)amino)-6-((2S)-2-methylmorpholin-4-yl)-1Hpyrimidin-2-one
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Fibrinolytic Agents
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Morpholines
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Protein Isoforms
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Pyrimidinones
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Class I Phosphatidylinositol 3-Kinases
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p110delta protein, rat
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1-Phosphatidylinositol 4-Kinase