Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 9, Pages 3933-3957Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00233
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Funding
- NIH [R01 GM104366, R01 GM121075]
- Alzheimer's & Related Diseases Research Award Fund
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Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with its five G-protein coupled receptors (S1P(1)-5) to regulate cell growth and survival and has been implicated in a variety of diseases including cancer and sickle cell disease. As the key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmaceutical inhibition. In this article, we describe the design, synthesis, and biological evaluation of aminothiazole-based guanidine inhibitors of SphK. Surprisingly, combining features of reported SphK1 inhibitors generated SphK1/2 dual inhibitor 20l (SLC4011540) (hSphK1 K-i = 120 nM, hSphK2 K-i = 90 nM) and SphK2 inhibitor 20dd (SLC4101431) (K-i = 90 nM, 100-fold SphK2 selectivity). These compounds effectively decrease S1P levels in vitro. In vivo administration of 20dd validated that inhibition of SphK2 increases blood S1P levels.
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