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

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.