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

Theodore C Jessop, 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, Theodore C Jessop, 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

Index: Bioorg. Med. Chem. Lett. 19(23) , 6784-7, (2009)

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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.