Peptidic renin inhibitors

Many companies have tried to develop peptidic renin inhibitors. Unfortunately these are rather large molecules and not unexpectedly poor absorption was often observed. The role of physicochemical properties has been discussed for this class of compounds. One of the conclusions was that compounds with higher lipophilicity were better absorbed from the intestine [29]. Absorption and bile elimination rate are both MW-dependent. Lower MW results in better absorption and less bile excretion. The combined influence of molecular size and lipophilicity on absorption of a series of renin inhibitors can be seen from Figure 1.7. The observed iso-size curves are believed to be part of a general sigmoidal relationship between permeability and lipophilicity [30-31] (for further details see Chapter 3). 

In this work we will focus on the use of the cubic phase as a delivery system for oligopeptides - Desmopressin, Lysine Vasopressin, Somatostatin and the Renin inhibitor H214/03. The amino acid sequences of these peptides are given in Table I. The work focuses on the cubic phase as a subcutaneous or intramuscular depot for extended release of peptide drugs, and as a vehicle for peptide uptake in the Gl-tract. Several examples of how the peptide drugs interact with this lipid-water system will be given in terms of phase behaviour, peptide self-diffusion, in vitro and in vivo release kinetics, and the ability of the cubic phase to protect peptides from enzymatic degradation in vitro. Part of this work has been described elsewhere (4-6). 

There have been sustained efforts in recent years to use the carrier systems of the brush-border membrane of intestinal mucosa to increase absorption of orally administered drugs [29] [30]. One system of particular interest is the intestinal peptide carrier (hPEPTl) whose physiological function is the absorption of di- and tripeptides and whose xenobiotic substrates include /3-lactam antibiotics, renin inhibitors, and angiotensin-converting enzyme (ACE) inhibitors [31]. 

A few interesting glyceride prodrugs of peptides can be found in the literature. For example, the pentapeptide renin inhibitor isovaleryl-Phe-Nle-Sta-Ala-Sta was derivatized to the l,3-dipalmitoyl-2-glyceryl ester (8.40) in the hope of improving oral bioavailability [55]. The in vitro results were... 

A rather new development is the orally available renin inhibitor aliskiren. It was approved by the U.S. Food and Drug Administration in 2007 for the treatment of hypertension. As mentioned above renin is a protease released on various stimuli from the jux-taglomerula apparatus in the kidney. Its release is the limiting step in the whole renin-angiotensin cascade. Since renin is highly substrate-specific its inhibition can be expected to have very little unspecific side effects. The result of an effective blockade of this enzyme is a reduced angiotensin I and angiotensin II formation. In contrast to ACE-inhibition or ATi-receptor blockade, the plasma concentrations of both peptides stay low. No interaction with other systems like the Kallikrenin-Bradykinin system seems to take place. 

Peptides, when administered orally, are susceptible to degradation in the stomach by gastric enzymes and the proteinases of the pancreas and brush border of the small intestine. Their lifetimes in the plasma are often short due to rapid proteolysis and other metabolic processes. Early efforts were made to improve the resistance of renin inhibitors to hydrolysis in vivo by the use of blocking groups at the Eland C-terminii [39] and replacement of susceptible peptide bonds other than the renin cleavage site. Studies of SAR have shown that various N- and C-terminal groups, some based on the morpholine nucleus and derivatives of it, have a favorable effect on the duration of inhibition in the... 

The intense interest in y - am i n o - (i -hydroxy acid related peptides has led to a great deal of effort devoted to their synthesis. Statine analogues Ahppa (11), Achpa (12), and Dahoa (13) (Scheme 2), which correspond to the replacement of the chain equivalent of leucine in statine by those of phenylalanine, cyclohexylalanine, and lysine, respectively, were used to synthesize inhibitors of pepsin, renin, and penicillinopepsinJ1314] With the objective of developing highly specific inhibitors, C2-substituted analogues have also been introduced into short, substrate-derived inhibitors, e.g. the a,a-difluoro statine 14 in renin inhibitors,1151 and N -substituted statine derivatives like 15 in HIV-1 protease inhibitors.[16]... 

B. Weidmann, Renin inhibitors, from transition state analogs and peptide mimetics to blood pressure lowering drugs, Chimia 1991, 45, 367-376. 

Renin inhibitors block the function of renin, the enzyme that converts angiotensinogen to angiotensin I. The inhibition of renin represents a relatively new approach to controlling hypertension. To date, the only widely approved renin inhibitor is aliskiren (Tektuma, A.130) (Figure A.36). Renin cleaves peptide bonds. Not surprisingly, aliskiren, as a pepti-domimetic, has a distinct peptide appearance. 

Derivatizations in the N-terminal sequence of human angiotensinogen led to weakly active renin inhibitors 183). According to Szelke et al.l84), highly active substrate analogs with modified peptide linkage ( CH2 NH—) were formed by reduction of the CO—NH bond in Leu-Leu or Phe-Phe (Table 2). 

Table 2. Renin inhibitors with a modified peptide linkage R = reduced peptide linkage...

By exchanging Leu10 for Sta in the N-terminal end of angiotensinogen, active renin inhibitors have been produced (Table 3)185 188>. It is assumed that statine corresponds to the tetrahedral intermediate during the enzymatic hydrolysis of the Leu10-Valu peptide linkage in angiotensinogen. 

Conjugated esters are a third class of substrates well suited for the AA. The (3-amino-a-hydroxy esters 68-71, resulting from the AA with PHAL ligands, are components of several small bioactive peptides, like the renin inhibitor KRI1314... 

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