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Wellaway CR, Baldwin IR, Bamborough P, et al. Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism. J Med Chem. 2021;doi: 10.1021/acs.jmedchem.1c01765.
Wellaway, C. R., Baldwin, I. R., Bamborough, P., Barker, D., Bartholomew, M. A., Chung, C. W., Dümpelfeld, B., Evans, J. P., Fazakerley, N. J., Homes, P., Keeling, S. P., Lewell, X. Q., McNab, F. W., Morley, J., Needham, D., Neu, M., van Oosterhout, A. J. M., Pal, A., Reinhard, F. B. M., Rianjongdee, F., Robertson, C. M., Rowland, P., Shah, R. R., Sherriff, E. B., Sloan, L. A., Teague, S., Thomas, D. A., Wellaway, N., Wojno-Picon, J., Woolven, J. M., & Coe, D. M. (2021). Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism. Journal of medicinal chemistry, . https://doi.org/10.1021/acs.jmedchem.1c01765
Wellaway, Christopher R, et al. "Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism." Journal of medicinal chemistry vol. (2021). doi: https://doi.org/10.1021/acs.jmedchem.1c01765
Wellaway CR, Baldwin IR, Bamborough P, Barker D, Bartholomew MA, Chung CW, Dümpelfeld B, Evans JP, Fazakerley NJ, Homes P, Keeling SP, Lewell XQ, McNab FW, Morley J, Needham D, Neu M, van Oosterhout AJM, Pal A, Reinhard FBM, Rianjongdee F, Robertson CM, Rowland P, Shah RR, Sherriff EB, Sloan LA, Teague S, Thomas DA, Wellaway N, Wojno-Picon J, Woolven JM, Coe DM. Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism. J Med Chem. 2021 Dec 20; doi: 10.1021/acs.jmedchem.1c01765. Epub 2021 Dec 20. PMID: 34928601.
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J Med Chem. 2021 Dec 20; doi: 10.1021/acs.jmedchem.1c01765. Epub 2021 Dec 20.

Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism.

Journal of medicinal chemistry

Christopher R Wellaway, Ian R Baldwin, Paul Bamborough, Daniel Barker, Michelle A Bartholomew, Chun-Wa Chung, Birgit Dümpelfeld, John P Evans, Neal J Fazakerley, Paul Homes, Steven P Keeling, Xiao Q Lewell, Finlay W McNab, Joanne Morley, Deborah Needham, Margarete Neu, Antoon J M van Oosterhout, Anshu Pal, Friedrich B M Reinhard, Francesco Rianjongdee, Craig M Robertson, Paul Rowland, Rishi R Shah, Emma B Sherriff, Lisa A Sloan, Simon Teague, Daniel A Thomas, Natalie Wellaway, Justyna Wojno-Picon, James M Woolven, Diane M Coe

Affiliations

  1. GSK, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
  2. Cellzome GmbH, A GlaxoSmithKline Company, Meyerhofstraße 1, 69117 Heidelberg, Germany.

PMID: 34928601 DOI: 10.1021/acs.jmedchem.1c01765

Abstract

The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung.

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