Design and synthesis of pyrazolopyridine derivatives as sphingosine 1-phosphate receptor 2 ligands

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Luo, Zonghua¹  Yue, Xuyi¹  Yang, Hao¹  Liu, Hui¹  Klein, Robyn S.^2,3,4  Tu, Zhude¹ 

[1] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Dept Neurosci, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

关键词: Sphingosine 1-phosphate receptor 2;    Multiple sclerosis;    Binding affinities;    Selectivity;   

DOI  :  10.1016/j.bmcl.2017.12.010

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free