Discovery of novel S1P2 antagonists. Part 2: Improving the profile of a series of 1,3-bis(aryloxy)benzene derivatives.

Our initial lead compound 2 was modified to improve its metabolic stability. The resulting compound 5 showed excellent metabolic stability in rat and human liver microsomes. We subsequently designed and synthesized a hybrid compound of 5 and the 1,3-bis(aryloxy) benzene derivative 1 , which was previously reported by our group to be an S1P 2 antagonist. This hybridization reaction gave compound 9 , which showed improved S1P 2 antagonist activity and good metabolic stability. The subsequent introduction of a carboxylic acid moiety into 9 resulted in 14 , which showed potent antagonist activity towards S1P 2 with a much smaller species difference between human S1P 2 and rat S1P 2 . Compound 14 also showed good metabolic stability and an improved safety profile compared with compound 9 . [ABSTRACT FROM AUTHOR]