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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).
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2010 Mar 11; Vol. 53 (5), pp. 2239-49. - Publication Year :
- 2010
-
Abstract
- Protein kinase B (PKB or Akt) is an important component of intracellular signaling pathways regulating growth and survival. Signaling through PKB is frequently deregulated in cancer, and inhibitors of PKB therefore have potential as antitumor agents. The optimization of lipophilic substitution within a series of 4-benzyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided ATP-competitive, nanomolar inhibitors with up to 150-fold selectivity for inhibition of PKB over the closely related kinase PKA. Although active in cellular assays, compounds containing 4-amino-4-benzylpiperidines underwent metabolism in vivo, leading to rapid clearance and low oral bioavailability. Variation of the linker group between the piperidine and the lipophilic substituent identified 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as potent and orally bioavailable inhibitors of PKB. Representative compounds modulated biomarkers of signaling through PKB in vivo and strongly inhibited the growth of human tumor xenografts in nude mice at well-tolerated doses.
- Subjects :
- Animals
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacokinetics
Cell Line, Tumor
Cell Proliferation drug effects
Half-Life
Humans
Inhibitory Concentration 50
Magnetic Resonance Spectroscopy
Mice
Mice, Nude
Piperidines chemistry
Piperidines pharmacokinetics
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacokinetics
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Pyrimidines chemistry
Pyrimidines pharmacokinetics
Pyrroles chemistry
Pyrroles pharmacokinetics
Structure-Activity Relationship
Xenograft Model Antitumor Assays
Antineoplastic Agents chemical synthesis
Piperidines chemical synthesis
Protein Kinase Inhibitors chemical synthesis
Proto-Oncogene Proteins c-akt metabolism
Pyrimidines chemical synthesis
Pyrroles chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 53
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20151677
- Full Text :
- https://doi.org/10.1021/jm901788j