Design, structure-activity, and molecular modeling studies of potent renin inhibitory peptides having N-terminal Nin-For-Trp (Ftr): angiotensinogen congeners modified by P1-P1' Phe-Phe, Sta, Leu.psi.[CH(OH)CH2]Val or Leu.psi.[CH2NH]Val substitutions

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Abstract
A structure-conformation-activity investigation of several angiotensinogen (ANG) based inhibitors of human renin modified by either Phe-Phe, Sta, Leu.CHI.[CH2NH]Val, or Leu.CHI.[CH(OH)CH2]Val at the P1-P1'' cleavage site and P5 Trp(Nin-For) (Ftr) was performed. Specifically, Ac-Ftr-Pro-Phe-His-Phe-Phe-Val-Ftr-NH2 (1) provided a potent (K1 = 2.7 .times. 10-8 M) P1-P1'' Phe-Phe substituted renin inhibitor to initiate these studies. Substitution of the P1-P1'' Phe-Phe in compound 1 by Sta effected a 1000-fold increase in biological potency for the resultant octapeptide Ac-Ftr-Pro-Phe-His-Sta-Val-Ftr-NH2 (10; K1 = 6.7 .times. 10-11 M). Kinetic analysis of compound 10 showed it to be a competitive inhibitor of human renin catalyzed proteolysis of human ANG. Chemical modifications of the compounds 1 and 10 were evaluated on the basis of comparative human plasma renin inhibitory activities (IC50 values) in vitro. Carboxy-terminal truncation studies on compound 10 showed that the P2'' Val and P3'' Ftr residues could both be eliminated without significant loss (ca. 10-fold) in renin inhibitory activity as exemplified by the pentapeptide Ac-Ftr-Pro-Phe-His-Sta-NH2 (12; IC50 = 3.8 .times. 10-9 M). In addition, the corresponding P1-P1'' Leu.CHI.[CH(OH)CH2]Val and Leu.CHI.[CH2#H]Val derivatives of compound 12 were potent renin inhibitors: Ac-Ftr-Pro-Phe-His-Leu.CHI.[CH-(OH)CH2]Val-NH2 (13; IC50 = 3.1 .times. 10-10 M) and Ac-Ftr-Pro-Phe-His-Leu.CHI.[CH2NH]Val-NH2 (14; IC50 = 2.1 .times. 10-8 M). The structure-conformation-activity properties of the N-terminal Ftr substitution of these human renin inhibitors was examined by (1) comparative analysis of several analogues of 1 and Ac-Ftr-Pro-Phe-His-Sta-Ile-NH2 (17; IC50 = 1.0 .times. 10-10 M) having P5 site modifications by Trp, His, D-Ftr, and D-His, (2) deletion of the N-terminal Ftr residue from compounds by 12 and 17 to provide Ac-Pro-Phe-His-Sta-Ile-NH2 (16; IC50 = 3.1 .times. 10-8 M) and Ac-Pro-Phe-His-Sta-NH2 (15; IC50 = 5.6 .times. 10-6 M), and (3) computer modeling and dynamics studies of compounds 1 and 17 bound to CKH-RENIN, a simulated human remin model which were focused on identifying potential intermolecular interactions of their common P5-P2 sequence, Ac-Ftr-Pro-Phe-His, at the enzyme active site. Finally, the human renin specificity of selected congeners of compound 10 were determined by comparison to porcine kidney renin in vitro.

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