A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes

Abstract A series of AT 2 R ligands have been synthesized applying a quick, simple, and safe transesterification-type reaction whereby the sulfonyl carbamate alkyl tail of the selective AT 2 R antagonist C38 was varied. Furthermore, a limited number of compounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acid bioisosteres were synthesized and evaluated. By reducing the size of the alkyl chain of the sulfonyl carbamates, ligands 7a and 7b were identified with significantly improved in vitro metabolic stability in both human and mouse liver microsomes as compared to C38 while retaining the AT 2 R binding affinity and AT 2 R/AT 1 R selectivity. Eight of the compounds synthesized exhibit an improved stability in human microsomes as compared to C38.