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Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors |
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| Authors: | 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 Kenneth G Carson |
| Institution: | 1. Lexicon Pharmaceuticals, Princeton, NJ 08540, United States;2. Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States;3. ActiveSite, San Diego, CA 92121, United States |
| 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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