title: Synthesis and structure-activity relationships of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones as novel series of potent β isoform selective phosphatidylinositol 3-kinase inhibitors.
abstract: A series of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones with excellent enzyme inhibition, improved isoform selectivity, and excellent inhibition of downstream phosphorylation of AKT has been identified. Several compounds in the series demonstrated potent (∼ 0.100 μM IC(50)) growth inhibition in a PTEN deficient cancer cell line.
authors.affiliation: Cancer Metabolism Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. robert.m.sanchez@gsk.com
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sanchez
authors.forename: Karl
authors.initials: K
authors.lastname: Erhard
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Hardwicke
authors.forename: Hong
authors.initials: H
authors.lastname: Lin
authors.forename: Jeanelle
authors.initials: J
authors.lastname: McSurdy-Freed
authors.forename: Ramona
authors.initials: R
authors.lastname: Plant
authors.forename: Kaushik
authors.initials: K
authors.lastname: Raha
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Rominger
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schaber
authors.forename: Michael D
authors.initials: MD
authors.lastname: Spengler
authors.forename: Michael L
authors.initials: ML
authors.lastname: Moore
authors.forename: Hongyi
authors.initials: H
authors.lastname: Yu
authors.forename: Juan I
authors.initials: JI
authors.lastname: Luengo
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tedesco
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Rivero
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011743:Pyrimidines; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051059:PTEN Phosphohydrolase