Discovery of oxazole and triazole derivatives as potent and selective S1P1 agonists through pharmacophore-guided design

•A highly predictive 3D QSAR pharmacophore model of S1P1 agonists was developed.•35 target compounds were designed and synthesized based on the pharmacophore model.•Click chemistry reaction was used for rapidly assembly of molecules.•Most compounds were identified as potent and selective S1P1 agonists.•Three compounds showed good in vivo activities and favorable PK profiles.

We have discovered a series of triazole/oxazole-containing 2-substituted 2-aminopropane-1,3-diol derivatives as potent and selective S1P1 agonists (prodrugs) based on pharmacophore-guided rational design. Most compounds showed high affinity and selectivity for S1P1 receptor. Compounds 19b, 19d and 19p displayed clear dose responsiveness in the lymphocyte reduction model when administered orally at doses of 0.3, 1.0, 3.0 mg/kg with reduced effect on heart rate. These three compounds were also identified to have favorable pharmacokinetic properties.

Graphical abstractA series of triazole/oxazole-containing 2-substituted 2-aminopropane-1,3-diol derivatives were discovered as potent and selective S1P1 agonists based on pharmacophore-guided rational design.Figure optionsDownload full-size imageDownload as PowerPoint slide