Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxam ides as oral PI3K beta inhibitors, useful as antiplatelet agents

作者：Giordanetto Fabrizio^*; Barlaam Bernard; Berglund Susanne; Edman Karl; Karlsson Olle; Lindberg Jan; Nylander Sven; Inghardt Tord

来源：Bioorganic & Medicinal Chemistry Letters, 2014, 24(16): 3936-3943.

DOI：10.1016/j.bmcl.2014.07.007

• Phosphoinositide 3-kinase
• p110 beta
• PI3K beta
• Inhibitor
• Thromboembolism
• Anti-thrombotic agent
• Antiplatelet
• Insulin resistance

Optimization of AZD6482 (2), the first antiplatelet PI3K beta 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 PI3K alpha to minimize the risk for insulin resistance. Structure-based design and optimization of DMPK properties resulted in (R)-16, a novel, orally bioavailable PI3K beta inhibitor with potent in vivo anti-thrombotic effect with excellent separation to bleeding risk and insulin resistance.

• 出版日期2014-8-15