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...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2014-08, Vol.24 (16), p.3936-3943
Hauptverfasser:	Giordanetto, Fabrizio, Barlaam, Bernard, Berglund, Susanne, Edman, Karl, Karlsson, Olle, Lindberg, Jan, Nylander, Sven, Inghardt, Tord
Format:	Artikel
Sprache:	eng
Schlagworte:	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
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2014.07.007