title: Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers.
abstract: Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kβ activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kβ/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.
authors.affiliation: Centre de Recherches, AstraZeneca , Z. I. La Pompelle, Chemin de Vrilly, BP 1050, 51689 Reims Cedex 2, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Barlaam
authors.forename: Sabina
authors.initials: S
authors.lastname: Cosulich
authors.forename: Sébastien
authors.initials: S
authors.lastname: Degorce
authors.forename: Martina
authors.initials: M
authors.lastname: Fitzek
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
authors.forename: Urs
authors.initials: U
authors.lastname: Hancox
authors.forename: Christine
authors.initials: C
authors.lastname: Lambert-van der Brempt
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lohmann
authors.forename: Mickaël
authors.initials: M
authors.lastname: Maudet
authors.forename: Rémy
authors.initials: R
authors.lastname: Morgentin
authors.forename: Marie-Jeanne
authors.initials: MJ
authors.lastname: Pasquet
authors.forename: Aurélien
authors.initials: A
authors.lastname: Péru
authors.forename: Patrick
authors.initials: P
authors.lastname: Plé
authors.forename: Twana
authors.initials: T
authors.lastname: Saleh
authors.forename: Michel
authors.initials: M
authors.lastname: Vautier
authors.forename: Mike
authors.initials: M
authors.lastname: Walker
authors.forename: Lara
authors.initials: L
authors.lastname: Ward
authors.forename: Nicolas
authors.initials: N
authors.lastname: Warin
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002867:Chromones / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000737:chemistry / Q000188:drug therapy*; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013329:Structure-Activity Relationship
chemical_list: C000595972:AZD8186; D000814:Aniline Compounds; D002867:Chromones; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051059:PTEN Phosphohydrolase