2002 Volume 50 Issue 6 Pages 850-853
A series of four new potential renin inhibitors has been synthesized. The structure of the compounds was designed in such a way as to produce agents resistant to enzymatic degradation, metabolically stable, possibly potent and with improved oral absorption. All positions of the 8—13 fragment of the human angiotensinogen were occupied by unnatural units (two unnatural amino acids in positions P3 and P2 and two pseudodipeptides in positions P1–P1′ and P2′–P3′). Both N- and C-terminal functions of the inhibitors were blocked with tert-Boc and ethyl ester groups. Their hydrophobicity evaluated as a log P value, calculated by a computer method, was 6.57 and 6.08 respectively. All peptides were obtained by the carbodiimide method in solution and purified by chromatography on the SiO2 column. Their resistance to enzymatic degradation was assayed by determination of stability against chymotrypsin activity. The potency was measured in vitro by a spectrofluorimetric method (assay of Leu-Val-Tyr-Ser released from the N-acetyltetradecapeptide substrate by renin in the presence of the inhibitor). All inhibitors were stable to chymotrypsin. Their IC50 (M/l) values were: 9.6×10−4 (12), 1.6×10−5 (17), 1.0×10−5 (22) and 1.0×10−5 (23) respectively.
