Hit-to-lead evaluation of a novel class of sphingosine 1-phosphate lyase inhibitors
| Autor: | Kara L. Queeney, Maria A. Argiriadi, Anil Vasudevan, Jürgen Dinges, Eric Dominguez, Kelly E. Desino, Christopher M. Harris, Grier A. Wallace, Tegest Kebede, Hetal Patel, Denise C. Perron |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry Cell Pharmaceutical Science Biochemistry Structure-Activity Relationship 03 medical and health sciences Drug Discovery medicine Humans Enzyme Inhibitors Molecular Biology Cell potency Aldehyde-Lyases Chemistry Organic Chemistry Treatment options Hit to lead Metabolic stability Lyase In vitro Sphingosine 1 phosphate lyase 030104 developmental biology medicine.anatomical_structure Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:2297-2302 |
| ISSN: | 0960-894X |
| Popis: | 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 IC 50 = 1.0 μM, cell IC 50 = 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 IC 50 = 120 nM and cell potency to IC 50 = 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. |
| Databáze: | OpenAIRE |
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