Synthesis and renin inhibitory activity of angiotensinogen analogs having dehydrostatine, Lue.psi.[CH2S]Val, or Lue.psi.[CH2SO] Val at the Pt, P1' cleavage site

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Abstract
The synthesis and in vitro renin inhibitory potencies of angiotensinogen (ANG) analogues having amide (CONH) bond replacements at P1-P1'', the Leu-Val cleavage site, corresponding to Leu.psi.[CH2S]Val, Leu.psi.[Ch2SO]Val, and the tans olefinic analogue of statine (Sta), 4(S)-amino-6-methyl-2(E)-heptenoic acid (dehydrostatine, Dhs), are reported. These are compared to P1-P1'' Leu.psi.[Ch2NH]Val-, Sta-, or Phe-Phe-substituted analogues of the same template. The Dhs pseudodipeptide was found to be an adequate mimic of a trans CONH bond and gave a peptide, H-Pro-His-Pro-Phe-His-Dhs-Ile-His-D-Lys-OH, approximately equal in potency to a Phe-Phe-containing inhibitor, but 200-fold less potent than its Sta-substituted congener. That the enhanced potency of the Sta-containing peptide most likely depends on hydrogen bonding as well as tetrahedral geometry is indicated by the 50-100-fold lower potency of the tetrahedral Leu.phi.[Ch2S]Val and Leu.phi.[CH2SO]Val analogues as compared to the Leu.phi.[CH2NH]Val-containing congener.