Discovery of phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, an effective antithrombotic agent without associated bleeding and insulin resistance

  • Bioorg Med Chem Lett. 2012 Nov 1;22(21):6671-6. doi: 10.1016/j.bmcl.2012.08.102.
Fabrizio Giordanetto  1 ,  Andreas Wållberg ,  Saswati Ghosal ,  Tommy Iliefski ,  Johan Cassel ,  Zhong-Qing Yuan ,  Henrik von Wachenfeldt ,  Søren M Andersen ,  Tord Inghardt ,  Anders Tunek ,  Sven Nylander
Affiliations
  • 1. Medicinal Chemistry, AstraZeneca R&D, CVGI iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. [email protected]
PMID: 23010262 DOI: 10.1016/j.bmcl.2012.08.102
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.