Pyrrolidine analogs of arylceramide HPA-12

: Conformational constraint is the usual way to modify the properties of bioactive molecules. In some cases, such modification improves their activity as well as their affinity for their biological target. At the beginning of the millennium, the ( R,R )-HPA-12 was found to be the first antagonist of ceramide transporter CERT, which has been identified as a key factor for the ER-to-Golgi trafficking of ceramides. Ten years later, we have revised the stereochemistry of the most active HPA-12 diastereomer to ( R , S )-diastereomer and developed synthesis of more potent alkyl substituted HPA-12 analogs. In this contribution, we would like to describe a straightforward approach to the enantiomerically pure constraint pyrrolidine analogs of both ( R,S )-HPA-12 and ( R,R )-HPA-12 starting from 3-substituted pyroglutamic acids easily accessible via our methodology. The results of the binding assays to the CERT protein will be discussed.