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.

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.

[1]  Tracey Clark,et al.  Design of selective, ATP-competitive inhibitors of Akt. , 2010, Journal of medicinal chemistry.

[2]  Sydney L. Stoops,et al.  Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape , 2011, Expert opinion on therapeutic patents.

[3]  Ian Collins,et al.  Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration. , 2008, Journal of medicinal chemistry.

[4]  Jing Li,et al.  Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background , 2012, Molecular Cancer Therapeutics.

[5]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[6]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[7]  Ian Collins,et al.  Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design. , 2007, Journal of medicinal chemistry.

[8]  Marcel L Verdonk,et al.  Identification of inhibitors of protein kinase B using fragment-based lead discovery. , 2007, Journal of medicinal chemistry.

[9]  Matthew R. Lee,et al.  Design and synthesis of novel amide AKT1 inhibitors with selectivity over CDK2. , 2011, Bioorganic & medicinal chemistry letters.

[10]  D. Alessi,et al.  The nuts and bolts of AGC protein kinases , 2010, Nature Reviews Molecular Cell Biology.

[11]  B. Hemmings,et al.  PIKKing on PKB: regulation of PKB activity by phosphorylation. , 2009, Current opinion in cell biology.

[12]  R. Figlin,et al.  Akt inhibitors in clinical development for the treatment of cancer , 2010, Expert opinion on investigational drugs.

[13]  G. Aherne,et al.  Discovery of 4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides As Selective, Orally Active Inhibitors of Protein Kinase B (Akt)† , 2010, Journal of medicinal chemistry.

[14]  Tyler T. Risom,et al.  Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[15]  K. Hashimoto,et al.  Cardiovascular effects of Y-27632, a selective Rho-associated kinase inhibitor, assessed in the halothane-anesthetized canine model. , 2003, European journal of pharmacology.

[16]  P. Majumder,et al.  MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted Drugs In vitro and In vivo , 2010, Molecular Cancer Therapeutics.

[17]  Jun Liang,et al.  Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. , 2012, Journal of medicinal chemistry.