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

doi:10.1016/j.bmcl.2009.09.081

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

Journal article

Peer reviewed

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, …

Bioorganic & medicinal chemistry letters, Vol.19(23), pp.6784-6787

2009

DOI: https://doi.org/10.1016/j.bmcl.2009.09.081

PMID: 19836232

Abstract

Deoxycytidine kinase

Cancer

Immunology

Pharmacokinetics

Virology

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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Title: Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors
Creators: Theodore C Jessop - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
James E Tarver - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Marianne Carlsen - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Amy Xu - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Jason P Healy - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Alexander Heim-Riether - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Qinghong Fu - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Jerry A Taylor - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
David J Augeri - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Min Shen - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Terry R Stouch - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Ronald V Swanson - ActiveSite, San Diego, CA 92121, United States
Leslie W Tari - ActiveSite, San Diego, CA 92121, United States
Michael Hunter - ActiveSite, San Diego, CA 92121, United States
Isaac Hoffman - ActiveSite, San Diego, CA 92121, United States
Philip E Keyes - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Xuan-Chuan Yu - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
Maricar Miranda - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
Qingyun Liu - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
Jonathan C Swaffield - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
S David Kimball - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Amr Nouraldeen - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
Alan G.E Wilson - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
Ann Marie DiGeorge Foushee - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
Kanchan Jhaver - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
Rick Finch - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
Steve Anderson - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
Tamas Oravecz - Lexicon Pharmaceuticals, The Woodlands, TX 77381, United States
Kenneth G Carson - Lexicon Pharmaceuticals, Princeton, NJ 08540, United States
Publication Details: Bioorganic & medicinal chemistry letters, Vol.19(23), pp.6784-6787
Date published: 2009
Publisher: Elsevier Ltd
Academic Unit: Medicinal Chemistry (EMSOP)
Language: English
Resource Type: Journal article
Identifiers: 991031654749704646