New Renin Inhibitors with Pseudodipeptidic Units in P_1-P_<1'> and P_<2'>-P_<3'> Positions

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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 P_3 and P_2 and two pseudodipeptides in positions P_1-P_<1'> and P_<2'>-P_<3'>). Both N- and C-terminal functions of the inhibitors were blocked with tert-Boc and ethyl ester groups. Their hydrophobicity evaluated as a logP 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 chromatog-raphy on the SiO_2 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 IC_<-50> (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.
2002-06-01