Design, synthesis and docking-based 3D-QSAR study of novel 2-substituted 2-aminopropane-1,3-diols as potent and selective agonists of sphingosine-1-phosphate 1 (S1P1) receptor

Abstract

Spingosine-1-phosphate receptor 1 (S1P₁) has been actively pursued as an important therapeutic target in immune regulation. A series of 2-substituted 2-aminopropane-1,3-diols were designed and synthesized as selective S1P₁ agonists. Most of the compounds with a biphenyl ether scaffold showed moderate to excellent S1P₁/S1P₃ selectivity. Compound 40c is identified as a potent S1P₁ agonist with 350-fold S1P₁/S1P₃ selectivity. 39c, the alcohol form of 40c exerted good lymphopenia activity in vivo but with weak influence on heart rate. To investigate the SARs of 2-substituted 2-aminopropane-1,3-diols in more details, COMFA (q² = 0.547, r² = 0.986) and COMSIA (q² = 0.544, r² = 0.943) models were established based on molecular docking alignment, which were validated with high reliability in predicting activities of agonists. The 3D-QSAR models will be helpful in the design of novel, potent and selective S1P₁ agonists.