Conformationally restricted peptide isosteres. 2.1 Synthesis and in vitro potency of dipeptide renin inhibitors employing a 2-alkylsulfonyl-3-phenylcyclopropane carboxamide as a P3 amino acid replacement ☆

Abstract A series of dipeptide renin inhibitors employing a 2,3-disubstituted cyclopropane carboxamide at the P3 position of the molecule were prepared by coupling racemic(IS,2R,3R) 2-alkylsulfonyl-3-phenyl(or cyclohexyl)cyclopropanecarboxylic acid with the amino acid derivatives 11a–d. The individual diastereomers were separated and tested for in vitro potency. IC50 values ranged from 0.37 to 1.4 nM and 5.8 to 29 nm against purified, pH 6.0 and plasma, pH 7.4 human renin, respectively. In all examples, the more polar diastereomer was the most potent.