The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization

Tony Siu; Sathyajith E. Kumarasinghe; Michael D. Altman; Matthew Katcher; Alan Northrup; Catherine White; Craig Rosenstein; Anjili Mathur; Lin Xu; Grace Chan; Eric Bachman; Melaney Bouthillette; Christopher J. Dinsmore; C. Gary Marshall; Jonathan R. Young

doi:10.1016/j.bmcl.2014.02.011

The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization

Tony Siu^*, Sathyajith E. Kumarasinghe, Michael D. Altman, Matthew Katcher, Alan Northrup, Catherine White, Craig Rosenstein, Anjili Mathur, Lin Xu, Grace Chan, Eric Bachman, Melaney Bouthillette, Christopher J. Dinsmore, C. Gary Marshall, Jonathan R. Young

^*Corresponding author for this work

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

5 Scopus citations

Abstract

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.

Original language	English (US)
Pages (from-to)	1466-1471
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2014.02.011
State	Published - Mar 15 2014

Keywords

JAK2
Kinase partition index
Kinase selectivity
Kinases
Ligand binding affinity
Molecular modeling
Water interaction

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmaceutical Science
Organic Chemistry

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10.1016/j.bmcl.2014.02.011

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Siu, T., Kumarasinghe, S. E., Altman, M. D., Katcher, M., Northrup, A., White, C., Rosenstein, C., Mathur, A., Xu, L., Chan, G., Bachman, E., Bouthillette, M., Dinsmore, C. J., Marshall, C. G., & Young, J. R. (2014). The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization. Bioorganic and Medicinal Chemistry Letters, 24(6), 1466-1471. https://doi.org/10.1016/j.bmcl.2014.02.011

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abstract = "This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.",

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author = "Tony Siu and Kumarasinghe, {Sathyajith E.} and Altman, {Michael D.} and Matthew Katcher and Alan Northrup and Catherine White and Craig Rosenstein and Anjili Mathur and Lin Xu and Grace Chan and Eric Bachman and Melaney Bouthillette and Dinsmore, {Christopher J.} and Marshall, {C. Gary} and Young, {Jonathan R.}",

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Siu, T, Kumarasinghe, SE, Altman, MD, Katcher, M, Northrup, A, White, C, Rosenstein, C, Mathur, A, Xu, L, Chan, G, Bachman, E, Bouthillette, M, Dinsmore, CJ, Marshall, CG & Young, JR 2014, 'The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization', Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 6, pp. 1466-1471. https://doi.org/10.1016/j.bmcl.2014.02.011

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AU - Siu, Tony

AU - Kumarasinghe, Sathyajith E.

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AU - Katcher, Matthew

AU - Northrup, Alan

AU - White, Catherine

AU - Rosenstein, Craig

AU - Mathur, Anjili

AU - Xu, Lin

AU - Chan, Grace

AU - Bachman, Eric

AU - Bouthillette, Melaney

AU - Dinsmore, Christopher J.

AU - Marshall, C. Gary

AU - Young, Jonathan R.

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AB - This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.

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KW - Kinase selectivity

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KW - Ligand binding affinity

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The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization

Abstract

Keywords

ASJC Scopus subject areas

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