Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as oral PI3Kβ inhibitors, useful as antiplatelet agents
Optimization of AZD6482 (2), the first antiplatelet PI3Kβ inhibitor evaluated in man, focused on improving the pharmacokinetic profile to a level compatible with once daily oral dosing as well as achieving adequate selectivity towards PI3Kα to minimize the risk for insulin resistance. Structure-base...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-08, Vol.24 (16), p.3936-3943 |
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| container_end_page | 3943 |
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| container_issue | 16 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 24 |
| creator | Giordanetto, Fabrizio Barlaam, Bernard Berglund, Susanne Edman, Karl Karlsson, Olle Lindberg, Jan Nylander, Sven Inghardt, Tord |
| description | Optimization of AZD6482 (2), the first antiplatelet PI3Kβ inhibitor evaluated in man, focused on improving the pharmacokinetic profile to a level compatible with once daily oral dosing as well as achieving adequate selectivity towards PI3Kα to minimize the risk for insulin resistance. Structure-based design and optimization of DMPK properties resulted in (R)-16, a novel, orally bioavailable PI3Kβ inhibitor with potent in vivo anti-thrombotic effect with excellent separation to bleeding risk and insulin resistance. |
| doi_str_mv | 10.1016/j.bmcl.2014.07.007 |
| format | Article |
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| ispartof | Bioorganic & medicinal chemistry letters, 2014-08, Vol.24 (16), p.3936-3943 |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Administration, Oral Animals Anti-thrombotic agent Antiplatelet Dogs Dose-Response Relationship, Drug Drug Discovery Humans Inhibitor Insulin resistance Male Molecular Structure p110β Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide 3-kinase PI3Kβ Platelet Aggregation - drug effects Platelet Aggregation Inhibitors - administration & dosage Platelet Aggregation Inhibitors - chemistry Platelet Aggregation Inhibitors - pharmacology Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Structure-Activity Relationship Thromboembolism |
| title | Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as oral PI3Kβ inhibitors, useful as antiplatelet agents |
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