Design and Synthesis of Tri‐substituted Chiral Pyrrolidin‐2‐one Derivatives as CCR4 Antagonists

Abstract

AbstractA series of tri‐substituted chiral pyrrolidin‐2‐one derivatives have been designed and synthesized as CC chemokine receptor 4 (CCR4) antagonists. The structure of CCR4 was built by homology modeling. Asymmetric synthesis was applied to synthesize the R,R configuration chiral pyrrolidin‐2‐one scaffold. The stereoisomeric configurations of the compounds were identified by 2D 1H‐1H COSY spectroscopy and 1D NOESY spectroscopy. This method was more economical and convenient than traditional X‐ray single crystal diffraction. In addition, the interactions between these compounds and the N‐terminal extracellular tail of CCR4 were studied using capillary zone electrophoresis. The CCR4 chemotaxis inhibition effect was tested in CCR4‐transfected HEK293 cells. Several compounds showed potent activities as CCR4 antagonists. Among these compounds, 1c is the most active one. Its apparent binding constant of CZE experiment result is (1.569±0.11)×105 L·mol−1, and its percentage inhibition of the HEK293/CCR4 cells migration with the concentration of 1 µmol·L−1 in DMSO is 59%. And compound 1f has slightly higher affinity to N‐terminal of CCR4 according to its apparent binding constant than 1b because of the introduced ester linkage. Further studies on the mechanism of these compounds are in progress.