title: [3a,4]-Dihydropyrazolo[1,5a]pyrimidines: Novel, Potent, and Selective Phosphatidylinositol-3-kinase β Inhibitors.
abstract: A series of novel [3a,4]dihydropyrazolo[1,5a]pyrimidines were identified, which were highly potent and selective inhibitors of PI3Kβ. The template afforded the opportunity to develop novel SAR for both the hinge-binding (R3) and back-pocket (R4) substitutents. While cellular potency was relatively modest due to high protein binding, the series displayed low clearance in rat, mouse, and monkey.
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Yu
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Moore
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Karl
authors.initials: K
authors.lastname: Erhard
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Hardwicke
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Lin
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Luengo
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Jeanelle
authors.initials: J
authors.lastname: McSurdy-Freed
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Ramona
authors.initials: R
authors.lastname: Plant
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Junya
authors.initials: J
authors.lastname: Qu
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Raha
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Rominger
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schaber
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Spengler
authors.affiliation: Cancer Metabolism Chemistry, Cancer Metabolism Biology, Cancer Metabolism DMPK, Computational Chemistry, Platform Technology Sciences, and Screening and Compound Profiling, Platform Technology Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Rivero
keywords: PI3K-β inhibitor; PTEN-null; phosphatidylinositol-3-kinase; pyrazolopyrimidine; structure−activity relationship