title: Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as oral PI3Kβ inhibitors, useful as antiplatelet agents.
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.
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: fgiordanetto@tarosdiscovery.com.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Bernard
authors.initials: B
authors.lastname: Barlaam
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Berglund
authors.affiliation: Discovery Sciences, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Edman
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Karlsson
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Lindberg
authors.affiliation: Bioscience, AstraZeneca R&D, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nylander
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D, CVMD iMed, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: tord.inghardt@astrazeneca.com.
authors.forename: Tord
authors.initials: T
authors.lastname: Inghardt
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008297:Male; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010975:Platelet Aggregation Inhibitors; D047428:Protein Kinase Inhibitors
keywords: Anti-thrombotic agent; Antiplatelet; Inhibitor; Insulin resistance; PI3Kβ; Phosphoinositide 3-kinase; Thromboembolism; p110β