912762-45-9Relevant articles and documents
Hit-to-lead evaluation of a novel class of sphingosine 1-phosphate lyase inhibitors
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
, p. 2297 - 2302 (2016/04/20)
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.
