Design and synthesis of pyrazolopyridine derivatives as sphingosine 1-phosphate receptor 2 ligands |
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| Authors: | Zonghua Luo Xuyi Yue Hao Yang Hui Liu Robyn S. Klein Zhude Tu |
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| Affiliation: | 1. Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA;2. Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA;3. Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA;4. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA |
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| Abstract: | Eleven new sphingosine 1-phosphate receptor 2 (S1PR2) ligands were synthesized by modifying lead compound N-(2,6-dichloropyridin-4-yl)-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazine-1-carboxamide (JTE-013) and their binding affinities toward S1PRs were determined in vitro using [32P]S1P and cell membranes expressing recombinant human S1PRs. Among these ligands, 35a (IC50?=?29.1?±?2.6?nM) and 35b (IC50?=?56.5?±?4.0?nM) exhibit binding potency toward S1PR2 comparable to JTE-013 (IC50?=?58.4?±?7.4?nM) with good selectivity for S1PR2 over the other S1PRs (IC50?>?1000?nM). Further optimization of these analogues may identify additional and more potent and selective compounds targeting S1PR2. |
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| Keywords: | Sphingosine 1-phosphate receptor 2 Multiple sclerosis Binding affinities Selectivity |
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