Discovery of 4‑Amino‑<i>N</i>‑[(1<i>S</i>)‑1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7<i>H</i>‑pyrrolo[2,3‑<i>d</i>]pyrimidin-4-yl)piperidine-4-carboxamide
(AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases
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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