Discovery of AZD-2098 and AZD-1678, two potent and bioavailable CCR4 receptor antagonists

Kindon, Nicholas; Andrews, Glen; Baxter, Andrew; Cheshire, David; Hemsley, Paul; Johnson, Timothy; Liu, Yu-Zhen; McGinnity, Dermot; McHale, Mark; Mete, Antonio; Reuberson, James; Roberts, Bryan; Steele, John; Teobald, Barry; Unitt, John; Vaughan, Deborah; Walters, Iain; Stocks, Michael J.

Abstract

N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high throughput screen (HTS) of a sub-set of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs.

Citation

Kindon, N., Andrews, G., Baxter, A., Cheshire, D., Hemsley, P., Johnson, T., Liu, Y.-Z., McGinnity, D., McHale, M., Mete, A., Reuberson, J., Roberts, B., Steele, J., Teobald, B., Unitt, J., Vaughan, D., Walters, I., & Stocks, M. J. (in press). Discovery of AZD-2098 and AZD-1678, two potent and bioavailable CCR4 receptor antagonists. ACS Medicinal Chemistry Letters, 8(9), 981–986. https://doi.org/10.1021/acsmedchemlett.7b00315

• Journal Article Type: Article
• Acceptance Date: Sep 1, 2017
• Online Publication Date: Sep 1, 2017
• Deposit Date: Sep 8, 2017
• Publicly Available Date: Sep 2, 2018
• Journal: ACS Medicinal Chemistry Letters
• Electronic ISSN: 1948-5875
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 9
• Pages: 981–986
• DOI: https://doi.org/10.1021/acsmedchemlett.7b00315
• Keywords: Chemokine receptor 4; MDC; TARC; CCR4; Antagonist
• Public URL: https://nottingham-repository.worktribe.com/output/880038
• Publisher URL: https://doi.org/10.1021/acsmedchemlett.7b00315
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. ; To access the final edited and published work see https://doi.org/10.1021/acsmedchemlett.7b00315
• Contract Date: Sep 8, 2017