2. Academic Validation
  3. 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

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

  • J Med Chem. 2013 Mar 14;56(5):2059-73. doi: 10.1021/jm301762v.
Matt Addie 1,  Peter Ballard,  David Buttar,  Claire Crafter,  Gordon Currie,  Barry R Davies,  Judit Debreczeni,  Hannah Dry,  Philippa Dudley,  Ryan Greenwood,  Paul D Johnson,  Jason G Kettle,  Clare Lane,  Gillian Lamont,  Andrew Leach,  Richard W A Luke,  Jeff Morris,  Donald Ogilvie,  Ken Page,  Martin Pass,  Stuart Pearson,  Linette Ruston
Affiliations

Affiliation

  • 1 Oncology iMed, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
PMID: 23394218 DOI: 10.1021/jm301762v
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.

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