SAR studies of 3-arylpropionic acids as potent and selective agonists of sphingosine-1-phosphate receptor-1 (S1P1) with enhanced pharmacokinetic properties

Structure–activity relationship (SAR) studies of 3-arylpropionic acids—a class of novel S1P1 selective agonists—by introducing substitution to the propionic acid chain and replacing the adjacent phenyl ring with pyridine led to a series of modified 3-arylpropionic acids with enhanced half-life in rat. These analogs (e.g., cyclopropanecarboxylic acids) exhibited longer half-life in rat than did unmodified 3-arylpropionic acids. This result suggests that metabolic oxidation at the propionic acid chain, particularly at the C3 benzylic position of 3-arylpropionic acids, is probably responsible for their short half-life in rodent.

Graphical abstractStructure–activity relationship (SAR) studies of 3-arylpropionic acids—a class of novel S1P1 selective agonists—by introducing substitution to the propionic acid chain and replacing the adjacent phenyl ring with pyridine (indicated by alphabetic letters in the Figure) led to a series of modified 3-arylpropionic acids with enhanced half-life in rat. These analogs exhibited longer half-life in rat than did unmodified 3-arylpropionic acids, suggesting that metabolic oxidation on the propionic acid chain, particularly at the C3 benzylic position of 3-arylpropionic acids, is probably responsible for their short half-life in rodent.Figure optionsDownload full-size imageDownload as PowerPoint slide