Synthesis, resolution, and assignment of configuration of potent hypotensive retro-inverso bradykinin potentiating peptide 5a(BPP5a) analogues

Abstract

The effect on the biological activity of an inverted amide group as an isosteric replacement for the Phe-Ala scissile bond of the BPP_5a analogue [Phe³]BPP_5a has been studied. The synthesis of the retroinverso pentapeptide [gPhe³,(R,S)-mAla⁴]BPP_5a has been carried out in solution by coupling the pseudopeptide epimer HO-(R,S)-mAla-Pro-OBu^t to Glp-Lys(Boc)-gPhe-H·HCl, separation and identification of the resulting diastereoisomers [Lys²(Boc),gPhe³,(S)-mAla⁴,Pro⁵-OBu^t]BPP_5a and [Lys²(Boc),gPhe³,(R)-mAla⁴,Pro⁵-OBu^t]BPP_5a, and finally acidolytic cleavage. [gPhe³,(S)-mAla⁴]BPP_5a, a moderate inhibitor of angiotensin converting enzyme (ACE)in vitro(I₅₀= 14 × 10^–5M), was obtained and proved to be more potent than BPP_5a as a hypotensive in normotensive rats without manifesting the bradykinin potentiating action of the natural peptide.