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

Matt Addie; Peter Ballard; David Buttar; Claire Crafter; Gordon Currie; Barry R. Davies; Judit Debreczeni; Hannah Dry; Philippa Dudley; Ryan Greenwood; Paul D. Johnson; Jason G. Kettle; Clare Lane; Gillian Lamont; Andrew Leach; Richard W A Luke; Jeff Morris; Donald Ogilvie; Ken Page; Martin Pass; Stuart Pearson; Linette Ruston

doi:10.1021/jm301762v

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

Matt Addie
, Peter Ballard
, David Buttar
, Claire Crafter
, Gordon Currie
, Barry R. Davies
, Judit Debreczeni
, Hannah Dry
, Philippa Dudley
, Ryan Greenwood
, Paul D. Johnson
, Jason G. Kettle
, Clare Lane
, Gillian Lamont
, Andrew Leach
, Richard W A Luke
, Jeff Morris
, Donald Ogilvie
, Ken Page
, Martin Pass

Stuart Pearson, Linette Ruston

Research output: Contribution to journal › Article › peer-review

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. © 2013 American Chemical Society.

Original language	English
Pages (from-to)	2059-2073
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	5
DOIs	https://doi.org/10.1021/jm301762v https://doi.org/10.1021/jm301762v
Publication status	Published - 14 Mar 2013

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Manchester Cancer Research Centre

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Addie, M., Ballard, P., Buttar, D., Crafter, C., Currie, G., Davies, B. R., Debreczeni, J., Dry, H., Dudley, P., Greenwood, R., Johnson, P. D., Kettle, J. G., Lane, C., Lamont, G., Leach, A., Luke, R. W. A., Morris, J., Ogilvie, D., Page, K., ... Ruston, L. (2013). 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. Journal of Medicinal Chemistry, 56(5), 2059-2073. https://doi.org/10.1021/jm301762v, https://doi.org/10.1021/jm301762v

@article{7d7156202ed74959bffc78410f2f49c4,

title = "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",

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. {\textcopyright} 2013 American Chemical Society.",

author = "Matt Addie and Peter Ballard and David Buttar and Claire Crafter and Gordon Currie and Davies, \{Barry R.\} and Judit Debreczeni and Hannah Dry and Philippa Dudley and Ryan Greenwood and Johnson, \{Paul D.\} and Kettle, \{Jason G.\} and Clare Lane and Gillian Lamont and Andrew Leach and Luke, \{Richard W A\} and Jeff Morris and Donald Ogilvie and Ken Page and Martin Pass and Stuart Pearson and Linette Ruston",

year = "2013",

month = mar,

day = "14",

doi = "10.1021/jm301762v",

language = "English",

volume = "56",

pages = "2059--2073",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "5",

}

Addie, M, Ballard, P, Buttar, D, Crafter, C, Currie, G, Davies, BR, Debreczeni, J, Dry, H, Dudley, P, Greenwood, R, Johnson, PD, Kettle, JG, Lane, C, Lamont, G, Leach, A, Luke, RWA, Morris, J, Ogilvie, D, Page, K, Pass, M, Pearson, S & Ruston, L 2013, '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', Journal of Medicinal Chemistry, vol. 56, no. 5, pp. 2059-2073. https://doi.org/10.1021/jm301762v, https://doi.org/10.1021/jm301762v

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. / Addie, Matt; Ballard, Peter; Buttar, David et al.
In: Journal of Medicinal Chemistry, Vol. 56, No. 5, 14.03.2013, p. 2059-2073.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Addie, Matt

AU - Ballard, Peter

AU - Buttar, David

AU - Crafter, Claire

AU - Currie, Gordon

AU - Davies, Barry R.

AU - Debreczeni, Judit

AU - Dry, Hannah

AU - Dudley, Philippa

AU - Greenwood, Ryan

AU - Johnson, Paul D.

AU - Kettle, Jason G.

AU - Lane, Clare

AU - Lamont, Gillian

AU - Leach, Andrew

AU - Luke, Richard W A

AU - Morris, Jeff

AU - Ogilvie, Donald

AU - Page, Ken

AU - Pass, Martin

AU - Pearson, Stuart

AU - Ruston, Linette

PY - 2013/3/14

Y1 - 2013/3/14

N2 - 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. © 2013 American Chemical Society.

AB - 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. © 2013 American Chemical Society.

U2 - 10.1021/jm301762v

DO - 10.1021/jm301762v

M3 - Article

SN - 0022-2623

VL - 56

SP - 2059

EP - 2073

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

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

Abstract

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