title: Discovery of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours.
abstract: Starting from TGX-221, we designed a series of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as potent and selective PI3Kβ/δ inhibitors. Structure-activity relationships and structure-property relationships around the aniline and the amide substituents are discussed. We identified compounds 17 and 18, which showed profound pharmacodynamic modulation of phosphorylated Akt in the PC3 prostate tumour xenograft, after a single oral dose. Compound 17 also gave significant inhibition of tumour growth in the PC3 prostate tumour xenograft model after chronic oral dosing.
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Electronic address: bernard.barlaam2@astrazeneca.com.
authors.forename: Bernard
authors.initials: B
authors.lastname: Barlaam
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Sabina
authors.initials: S
authors.lastname: Cosulich
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Degorce
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Martina
authors.initials: M
authors.lastname: Fitzek
authors.affiliation: AstraZeneca R&D, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
authors.affiliation: AstraZeneca R&D, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Tord
authors.initials: T
authors.lastname: Inghardt
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Hennequin
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Urs
authors.initials: U
authors.lastname: Hancox
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lambert-van der Brempt
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Morgentin
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pass
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Plé
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Twana
authors.initials: T
authors.lastname: Saleh
authors.affiliation: AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Lara
authors.initials: L
authors.lastname: Ward
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors
keywords: PI3Kβ inhibitor; PTEN-deficient tumours; Rational design