Renin inhibitory peptide

Systematic modification of the octapeptide sequence from cin-giotensinogen (Figure 1) was undertaken to incorporate desirable properties into the peptide. Addition of a prolyl residue to the N-termlnus Improved solubility at physiologic pH, replacement of the leucyl-leucine sequence with phenylalanyl residues Improved inhibitory properties by forty-fold, and addition of a lysyl residue to the C-termlnus Increased solubility and extended half-life in vivo. These modifications yielded the Renin Inhibitory Peptide TriP) vdiich effectively blocks renin both in primates (11) and man (1 2). 

Thaisrivongs, S., Schostarez, H.J., Pals, D.T., et al. 1987. a,a-Difluoro-P-aminodeoxystatine-containing renin-inhibitory peptides. Journal of Medicinal Chemistry, 30 1837-42. 

RA Conradi, KF Wilkinson, BD Rush, AR Hilgers, MJ Ruwart, PS Burton. In vitro/in vivo models for peptide oral absorption comparison of Caco-2 cell permeability with rat intestinal absorption of renin inhibitory peptides. Pharm Res 10 1710-1714, 1993. 

Renin inhibitory peptide 184 is prepared from methyl butyl amine 182 and y-protected hydroxy acid 183 using DEPC. 

Linear renin inhibitory peptide 187 is synthesized by coupling of pyridine derivative 185 and substituted pyrrolidone carboxylic acid 186 using DEPC.71... 

Angiotensinogen analogs such as renin inhibitory peptide requires a key intermediate 199, which is prepared from imidazole carboxylic acid 197 and amine 198 in the presence of DEPC.75... 

Thaisrivongs, S., Blinn, J.R., Pals, D.T. and Turner, S.R. (1991) Conformationally constrained renin inhibitory peptides cyclic (3-l)-l-(carboxymethyl)-L-prolyl-L-phenylalanyl-L-histidinamide as a conformational restriction at the P2-P4 tripeptide portion of the angiotensinogen template, J. Med. Chem. 34 1276-1282. 

Syntheses of rac-la [8-10], (2 >la [11-13], (S)-la [13], (R)-P-(dimethylphenylsilyl)alanine [12], and (7 )-p-(methyldiphenylsilyl)alanine [12] have already been reported. In addition, the ethyl ester and the A -Fmoc and W-Boc derivatives of (K)-la, as well as renin inhibitory peptides bearing (7 )-la, have been described in the literature [14]. In contrast, germanium-containing a-amino acids have not yet been reported. 

Somatostatin has been found to inhibit the secretion of various other hormones such as thyrotropin, gastrin inhibitory peptide (GIP), vasoactive intestinal peptide (VIP), pancreozymin, secretin, motilin, gastrin, renin, ACTH in patients with ACTH-secreting pituitary adenoma and ACTH-secretion vitro and to effect exocrine pancreatic function and various GI functions. "21 The physiological significance of these findings is not clear at the present time. 

The angiotensin I-converting enzyme (ACE) participates in regulating blood pressure in the renin-angiotensin system. The inhibitors such as captopril (Suetsuna and Chen, 2001) and enalapril (Sawayama et ah, 1990) have been used as antih)/pertensive drugs. The ACE-inhibitory activity of various source have studied, and it was found that some ACE-inhibitory peptides were produced by enzymatic digestion of various marine food proteins, including tuna muscle (Kohama et al., 1991 Qndetti, 1977), sardine muscle (Suetsima et al., 1991), dried bonito (Yokoyama et ah, 1992), dried-salted fish (Astawan et ah, 1995), fish sauce (Okamoto et al, 1995), and fish water-soluble protein (Wako et ah, 1999). 

While Ferreira continued to focus on bradykinin. Sir John R. Vane (1927-2004) and Yeshwant S. Bakhle recognised that the snake venom also had an effect on the renin-angiotensin system. Miguel Ondetti (1930-2004) and David Cushman (1939-2000) at Squibb (now Bristol-Myers-Squibb) isolated and characterised six other ACE-inhibitory peptides, among them teprotide (IC50 250 nM). [7, 8]... 

Aoki M, Ohtsuka T, Yamada M, Ohba Y, Yoshtzaki H, Yasuno H, Sano T, Watanabe ], Yokose K, Seto H. Cyclothiazomycin, a novel polythiazoie-containing peptide with renin inhibitory... 

AHMOA is a key component of a renin inhibitory angiotensin peptide fragment. 

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