title: Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors.
abstract: From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.
authors.affiliation: Medicinal Chemistry Oncology Drug Discovery, Sanofi, Vitry-sur-Seine, France.
authors.forename: Victor
authors.initials: V
authors.lastname: Certal
authors.forename: Frank
authors.initials: F
authors.lastname: Halley
authors.forename: Angela
authors.initials: A
authors.lastname: Virone-Oddos
authors.forename: Fabienne
authors.initials: F
authors.lastname: Thompson
authors.forename: Bruno
authors.initials: B
authors.lastname: Filoche-Rommé
authors.forename: Youssef
authors.initials: Y
authors.lastname: El-Ahmad
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Carry
authors.forename: Cécile
authors.initials: C
authors.lastname: Delorme
authors.forename: Andreas
authors.initials: A
authors.lastname: Karlsson
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Abecassis
authors.forename: Loic
authors.initials: L
authors.lastname: Vincent
authors.forename: Hélène
authors.initials: H
authors.lastname: Bonnevaux
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Nicolas
authors.forename: Renaud
authors.initials: R
authors.lastname: Morales
authors.forename: Nadine
authors.initials: N
authors.lastname: Michot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vade
authors.forename: Audrey
authors.initials: A
authors.lastname: Louboutin
authors.forename: Sébastien
authors.initials: S
authors.lastname: Perron
authors.forename: Gilles
authors.initials: G
authors.lastname: Doerflinger
authors.forename: Bernadette
authors.initials: B
authors.lastname: Tric
authors.forename: Sylvie
authors.initials: S
authors.lastname: Monget
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.forename: Laurent
authors.initials: L
authors.lastname: Schio
mesh_terms: D000813:Anilides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D018360:Crystallography, X-Ray; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D051059:PTEN Phosphohydrolase / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011467:Prostate / Q000166:cytology / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D011744:Pyrimidinones; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human