Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 28, Issue 3, Pages 488-496Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.12.010
Keywords
Sphingosine 1-phosphate receptor 2; Multiple sclerosis; Binding affinities; Selectivity
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Funding
- National Multiple Sclerosis Society [RG150705331]
- USA Department of Energy (DOE) [DESC0008432, DESC0012737]
- USA National Institutes of Health (NIH) through the National Institute of Neurological Disorders and Stroke [NS075527]
- National Institute of Mental Health [MH092797]
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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 [P-32]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. (C) 2017 Elsevier Ltd. All rights reserved.
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