Hit-to-lead evaluation of a novel class of sphingosine 1-phosphate lyase inhibitors

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• 作者：Jurgen Dinges^a ; ; Christopher M. Harris^b ; Grier A. Wallace^c ; Maria A. Argiriadi^c ; Kara L. Queeney^b ; Denise C. Perron^b ; Eric Dominguez^b ; Tegest Kebede^b ; Kelly E. Desino^a ; Hetal Patel^a ; Anil Vasudevan^a
• 关键词：Sphingosine 1-phosphate lyase ; Hit-to-lead ; Inhibitor ; Parallel synthesis ; Structure-based design
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 May 2016
• 年：2016
• 卷：26
• 期：9
• 页码：2297-2302
• 全文大小：1783 K

文摘

Inhibition of sphingosine-1-phosphate lyase has recently been proposed as a potential treatment option for inflammatory disorders such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. In this report we describe our hit-to-lead evaluation of the isoxazolecarboxamide 6, a high-throughput screening hit (in vitro IC₅₀ = 1.0 μM, cell IC₅₀ = 1.8 μM), as a novel S1P lyase inhibitor. We were able to establish basic structure–activity relationships around 6 and succeeded in obtaining X-ray structural information which enabled structure-based design. With the discovery of 28, enzyme activity was quickly improved to IC₅₀ = 120 nM and cell potency to IC₅₀ = 230 nM. The main liability in the established isoxazolecarboxamide hit series was determined to be metabolic stability. In particular we identified that future lead-optimization efforts to overcome this problem should focus on blocking the N-dealkylation on the secondary amine.