Discovery of 4-Amino-N-[(1 S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7 H-pyrrolo [2, 3-d] pyrimidin-4-yl) piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, …

…, P Ballard, D Buttar, C Crafter, G Currie…

文献索引：Addie, Matt; Ballard, Peter; Buttar, David; Crafter, Claire; Currie, Gordon; Davies, Barry R.; Debreczeni, Judit; Dry, Hannah; Dudley, Philippa; Greenwood, Ryan; Johnson, Paul D.; Kettle, Jason G.; Lane, Clare; Lamont, Gillian; Leach, Andrew; Luke, Richard W. A.; Morris, Jeff; Ogilvie, Donald; Page, Ken; Pass, Martin; Pearson, Stuart; Ruston, Linette Journal of Medicinal Chemistry, 2013 , vol. 56, # 5 p. 2059 - 2073

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被引用次数: 34

摘要

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 ...