Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as oral PI3Kβ inhibitors, useful as antiplatelet agents

  • Bioorg Med Chem Lett. 2014 Aug 15;24(16):3936-43. doi: 10.1016/j.bmcl.2014.07.007.
Fabrizio Giordanetto  1 ,  Bernard Barlaam  2 ,  Susanne Berglund  3 ,  Karl Edman  4 ,  Olle Karlsson  3 ,  Jan Lindberg  3 ,  Sven Nylander  5 ,  Tord Inghardt  6
Affiliations
  • 1. Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: [email protected].
  • 2. Medicinal Chemistry, AstraZeneca R&D, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • 3. Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
  • 4. Discovery Sciences, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
  • 5. Bioscience, AstraZeneca R&D, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
  • 6. Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: [email protected].
PMID: 25042253 DOI: 10.1016/j.bmcl.2014.07.007
Abstract

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.

Keywords
Anti-thrombotic agent; Antiplatelet; Inhibitor; Insulin resistance; PI3Kβ; Phosphoinositide 3-kinase; Thromboembolism; p110β.