title: Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases.
abstract: Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.
authors: Oncology iMed, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
authors: Matt
authors: M
authors: Addie
authors: Peter
authors: P
authors: Ballard
authors: David
authors: D
authors: Buttar
authors: Claire
authors: C
authors: Crafter
authors: Gordon
authors: G
authors: Currie
authors: Barry R
authors: BR
authors: Davies
authors: Judit
authors: J
authors: Debreczeni
authors: Hannah
authors: H
authors: Dry
authors: Philippa
authors: P
authors: Dudley
authors: Ryan
authors: R
authors: Greenwood
authors: Paul D
authors: PD
authors: Johnson
authors: Jason G
authors: JG
authors: Kettle
authors: Clare
authors: C
authors: Lane
authors: Gillian
authors: G
authors: Lamont
authors: Andrew
authors: A
authors: Leach
authors: Richard W A
authors: RW
authors: Luke
authors: Jeff
authors: J
authors: Morris
authors: Donald
authors: D
authors: Ogilvie
authors: Ken
authors: K
authors: Page
authors: Martin
authors: M
authors: Pass
authors: Stuart
authors: S
authors: Pearson
authors: Linette
authors: L
authors: Ruston
mesh_terms: D000284:Administration, Oral; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D051057:Proto-Oncogene Proteins c-akt; C575618:capivasertib