Hit-to-lead evaluation of a novel class of sphingosine 1-phosphate lyase inhibitors. Issue 9 (1st May 2016)

• Record Type: Journal Article
• Authors: Dinges, Jurgen; Harris, Christopher M.; Wallace, Grier A.; Argiriadi, Maria A.; Queeney, Kara L.; Perron, Denise C.; Dominguez, Eric; Kebede, Tegest; Desino, Kelly E.; Patel, Hetal; Vasudevan, Anil
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 9(2016)
• Page Start: 2297
• Page End: 2302
• Publication Date: 2016-05-01
• Subjects: Sphingosine 1-phosphate lyase -- Hit-to-lead -- Inhibitor -- Parallel synthesis -- Structure-based design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.03.043
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 isoxazolecarboxamide6, 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 around6 and succeeded in obtaining X-ray structural information which enabled structure-based design. With the discovery of28, 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.