title: Discovery of 4-morpholino-pyrimidin-6-one and 4-morpholino-pyrimidin-2-one-containing Phosphoinositide 3-kinase (PI3K) p110β isoform inhibitors through structure-based fragment optimisation.
abstract: The discovery of 4-morpholino-pyrimidin-6-one and 4-morpholino-pyrimidin-2-one-containing inhibitors of Phosphoinositide 3-kinases (PI3K) p110β isoform is reported. Structure-based optimisation of the original fragment hit resulted in lead compounds with improvements in ligand efficiency, lipophilicity efficiency, p110β potency and selectivity over p110α.
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D, CVGI iMed, Mölndal, 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: Johan
authors.initials: J
authors.lastname: Cassel
authors.forename: Saswati
authors.initials: S
authors.lastname: Ghosal
authors.forename: Michael
authors.initials: M
authors.lastname: Kossenjans
authors.forename: Zhong-Qing
authors.initials: ZQ
authors.lastname: Yuan
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.forename: Lifeng
authors.initials: L
authors.lastname: Liang
mesh_terms: D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility
chemical_list: D004791:Enzyme Inhibitors; D009025:Morpholines; D010446:Peptide Fragments; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D011744:Pyrimidinones