title: 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.
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.
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D, CVGI iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. fabrizio.giordanetto@astrazeneca.com
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.forename: Andreas
authors.initials: A
authors.lastname: Wållberg
authors.forename: Saswati
authors.initials: S
authors.lastname: Ghosal
authors.forename: Tommy
authors.initials: T
authors.lastname: Iliefski
authors.forename: Johan
authors.initials: J
authors.lastname: Cassel
authors.forename: Zhong-Qing
authors.initials: ZQ
authors.lastname: Yuan
authors.forename: Henrik
authors.initials: H
authors.lastname: von Wachenfeldt
authors.forename: Søren M
authors.initials: SM
authors.lastname: Andersen
authors.forename: Tord
authors.initials: T
authors.lastname: Inghardt
authors.forename: Anders
authors.initials: A
authors.lastname: Tunek
authors.forename: Sven
authors.initials: S
authors.lastname: Nylander
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors*; D004285:Dogs; D055808:Drug Discovery; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007333:Insulin Resistance; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: C578928:4-(2-hydroxyethyl(1-naphthylmethyl)amino)-6-((2S)-2-methylmorpholin-4-yl)-1Hpyrimidin-2-one; D005343:Fibrinolytic Agents; D009025:Morpholines; D020033:Protein Isoforms; D011744:Pyrimidinones; D058534:Class I Phosphatidylinositol 3-Kinases; C488371:p110delta protein, rat; D019870:1-Phosphatidylinositol 4-Kinase