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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)

McHardy, Tatiana, Caldwell, John J., Cheung, Kwai-Ming, Hunter, Lisa J., Taylor, Kevin, Rowlands, Martin, Ruddle, Ruth, Henley, Alan, de Haven Brandon, Alexis, Valenti, Melanie, and others. (2010) 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). Journal of Medicinal Chemistry, 53 (5). pp. 2239-2249. ISSN 0022-2623. (doi:10.1021/jm901788j) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:58574)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://dx.doi.org/10.1021/jm901788j

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.

Item Type: Article
DOI/Identification number: 10.1021/jm901788j
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Michelle Garrett
Date Deposited: 11 Nov 2016 11:25 UTC
Last Modified: 13 Mar 2020 04:08 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/58574 (The current URI for this page, for reference purposes)
Garrett, Michelle D.: https://orcid.org/0000-0002-3939-1673
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