angiotensinogen has been researched along with statine* in 5 studies
5 other study(ies) available for angiotensinogen and statine
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New renin inhibitors containing novel analogues of statine.
Solid-phase methodology has been used to synthesize a series of peptides based on the N-terminal sequence of human angiotensinogen in which statine (Sta) or the novel analogues (3S,4S)-3,4-diamino- or (3R,4S)-3,4-diamino-6-methylheptanoic acid (Ads or R-Ads) and (3S,4S)-4-amino-3-aminomethyl- or (3R,4S)-4-amino-3-aminomethyl-6-methylheptanoic acid (Amd or R-Amd) replace either residue 10 or both residues 10-11 at the P1-P1' cleavage site. The synthesis of these novel analogues of statine together with biological results on the inhibition of human and rat renin by peptides derived from them is reported. The absolute stereochemistry of the (3S,4S) Ads was determined by an X-ray crystallographic analysis of its N gamma-Boc, B beta-Z, R(+)-1-methyl benzamide derivative. Peptide Boc-His-Pro-Phe-His-Sta-Val-Ile-His-NH2 (VI) is the best inhibitor of human renin containing Sta at position 10. However, peptides containing Ads and Amd gave better rat renin inhibitors than the corresponding Sta-containing peptides. Peptides Boc-His-Pro-Phe-His-Ads-Val-Ile-His-NH2 (VII) having Ads at position 10 had an IC50 of 12 nM against rat renin. Although Sta has come to be accepted as an isosteric replacement for a dipeptide unit rather than for a single amino acid residue, in our series of inhibitors Sta is more effective when replacing only the amino acid at position 10 in the natural angiotensinogen sequence. None of the peptides gave any effect in vivo in a hypertensive rat model. Topics: Amino Acid Sequence; Amino Acids; Angiotensinogen; Animals; Chromatography, High Pressure Liquid; Crystallization; Crystallography, X-Ray; Heptanoic Acids; Humans; Hydrogen Bonding; Mass Spectrometry; Models, Molecular; Molecular Structure; Peptides; Protease Inhibitors; Rats; Renin; Stereoisomerism | 1997 |
Potent in vivo inhibitors of rat renin: analogues of human and rat angiotensinogen sequences containing different classes of pseudodipeptides at the scissile site.
Using solid-phase methodology we have synthesised peptides based on the 8-14 or 6-14 human and rat angiotensinogen sequences, containing the following different isosteric units at the P1-P1' cleavage site: Leu-psi[CH2NH]Leu; Leu-psi[CH(OH)CH2]Val; Leu-psi[CH(OH)CH2]Leu and Leu-psi[CH(NH2)CH2]Val. In vitro, peptide Piv-His-Pro-Phe-His-Leu-psi[CH(OH)CH2]Leu-Tyr-Tyr-Ser-NH2(XXI) is the most potent inhibitor of rat plasma renin reported having an IC50 of 0.21 nM; it is a much weaker inhibitor of human renin (IC50 45 nM). Peptide Boc-His-Pro-Phe-His-Leu-psi[CH(OH)CH2] Leu-Val-Ile-His-NH2 (XX) was a highly effective inhibitor of rat renin in vivo. When infused (1 mg/kg/h) into two-kidney, one-clip chronic renal hypertensive rats, it lowered blood pressure and suppressed both plasma renin and angiotensin II. When given as a bolus (1 mg/kg) there was a divergence between the rapid rebound of renin levels and blood pressure, which remained suppressed. These results indicate that potent in vivo inhibitors of rat renin could be useful not only in examining the role of circulating renin but also in elucidating the equally important involvement of extracirculatory renin pools. Topics: Amino Acids; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Dipeptides; Humans; Kidney; Peptide Fragments; Protease Inhibitors; Rats; Renin | 1997 |
Synthesis and renin inhibitory activity of angiotensinogen analogues having dehydrostatine, Leu psi [CH2S]Val, or Leu psi [CH2SO]Val at the P1-P1' cleavage site.
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[CH2SO]Val, and the trans 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 psi[CH2S]Val and Leu psi[CH2SO]Val analogues as compared to the Leu psi[CH2NH]Val-containing congener. Topics: Amino Acids; Angiotensinogen; Chemical Phenomena; Chemistry; Dipeptides; Humans; Renin; Structure-Activity Relationship | 1988 |
alpha,alpha-Difluoro-beta-aminodeoxystatine-containing renin inhibitory peptides.
The preparations of sodium 4(S)-[(tert-butyloxycarbonyl)amino]-2,2-difluoro-3(S)- and -3(R)-[(4-methoxyphenyl)amino]-6-methylheptanoates (7a and 7b) from sodium 4(S)-[(tert-butyloxycarbonyl)amino]-2,2-difluoro-3(R)- and -3(S)-hydroxy-6-methylheptanoates (1a and 1b) are described. The key step involves the stereospecific intramolecular displacement via a Mitsunobu reaction for the conversion of a beta-hydroxy hydroxamate to a beta-lactam ring. Compounds 7a and 7b are useful as synthetic intermediates for the preparation of enzyme inhibitors that contain 3(S),4(S)- and 3(R),4(S)-diamino-2,2-difluoro-6-methylheptanoic acid inserts. Angiotensinogen analogues VII and VIII that contain these novel amino analogues of difluorostatine were shown to be inhibitors of the enzyme renin. The alpha,alpha-difluoro-beta-aminodeoxystatine-containing compounds were shown to be weaker inhibitors than the corresponding difluorostatine-containing congeners. Topics: Amino Acids; Angiotensinogen; Enzyme Inhibitors; Humans; Renin; Stereoisomerism | 1987 |
Comparison of angiotensinogen and tetradecapeptide as substrates for human renin. Substrate dependence of the mode of inhibition of renin by a statine-containing hexapeptide.
The kinetic properties of two different substrates for human renin, a synthetic tetradecapeptide and the natural substrate human angiotensinogen, have been compared. While the Vmax was similar for the two substrates, the Km values differed by a factor of 10, i.e., 11.7 +/- 0.7 microM (tetradecapeptide) and 1.0 +/- 0.1 microM (angiotensinogen). The mode of inhibition of renin by a statine (Sta)-containing hexapeptide, BW897C, that is a close structural analog of residues 8-13 of human angiotensinogen (Phe-His-Sta-Val-Ile-His-OMe), was determined for the two substrates. Competitive inhibition was observed when tetradecapeptide was the substrate (Ki = 2.0 +/- 0.2 microM), but a more complex mixed inhibition mode (Ki = 1.7 +/- 0.1 microM, Ki' = 3.0 +/- 0.23 microM) was found with angiotensinogen as substrate. This mixed inhibition probably results from the formation of an enzyme-inhibitor-substrate or enzyme-inhibitor-product complex and reflects the more extensive interactions that the protein angiotensinogen, as opposed to the small tetradecapeptide substrate, can make with renin. We conclude that the mixed inhibition observed when angiotensinogen is used as renin substrate could be important in the clinical application of renin inhibitors because it is less readily reversed by increased concentrations of substrate than is simple competitive inhibition. Topics: Amino Acids; Angiotensinogen; Humans; Kinetics; Oligopeptides; Renin; Substrate Specificity | 1987 |