Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors

  • Bioorg Med Chem Lett. 2009 Dec 1;19(23):6784-7. doi: 10.1016/j.bmcl.2009.09.081.
Theodore C Jessop  1 ,  James E Tarver ,  Marianne Carlsen ,  Amy Xu ,  Jason P Healy ,  Alexander Heim-Riether ,  Qinghong Fu ,  Jerry A Taylor ,  David J Augeri ,  Min Shen ,  Terry R Stouch ,  Ronald V Swanson ,  Leslie W Tari ,  Michael Hunter ,  Isaac Hoffman ,  Philip E Keyes ,  Xuan-Chuan Yu ,  Maricar Miranda ,  Qingyun Liu ,  Jonathan C Swaffield ,  S David Kimball ,  Amr Nouraldeen ,  Alan G E Wilson ,  Ann Marie Digeorge Foushee ,  Kanchan Jhaver ,  Rick Finch ,  Steve Anderson ,  Tamas Oravecz ,  Kenneth G Carson
Affiliations
PMID: 19836232 DOI: 10.1016/j.bmcl.2009.09.081
Abstract

A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.

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