Renin inhibitor development

For a series of renin inhibitors a good correlation between the measured membrane permeability and log D was found (r2 = 0.8). The model has been validated against a human perfusion model [10], as well as being extended by including molecular weight as a third parameter [27]. A further development of the model is to chronically cannulate the animals so that they can be allowed to recover [28]. This model should avoid any effects from the anesthetic on the absorption process. 

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). 

The use of substrate analogs has led to the rapid development of inhibitors for several highly specific proteases. Research from this laboratory on the development of renin Inhibitors, kalllkreln Inhibitors, and Inhibitors of IgA-) protease Is outlined below. 

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. 

As with ACE inhibitors, renin inhibitors should not be used in pregnancy, specifically the second and third trimesters, during which they will interfere with fetal kidney development. 

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]... 

Gupta, S.L, Patel, J.P, Jones, D.L, and Partipilo, R.W Parenteral formulation development of renin inhibitor Abbott 72517,J. Parent. Sci. Technol, 48, 86-91, March-April 1994. 

Other interesting hybrids between hydroxyethylene and hydroxyethylamine dipeptide isosteres have been reported. Getman et al (1993) developed a series of hydroxyethylureas that potently inhibited HIV-1 protease. The concept of these urea isosteres, first introduced as renin inhibitors, may be envisioned as a modification of the hydroxyethylene isostere (e.g., compound 22), in which the PV chiral a-car-bon is replaced with a trigonal nitrogen. One example of this class of inhibitors, SC-52151 (26) (Table III), inhibited HIV-1 protease with an IC50 value of 6 nMand blocked the cytopathic effect of HIV-1 in cell cul-... 

Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors. BMC Bioinformatics 12 Suppl 14, S4... 

Because of the similarity of the active sites of renin and HIV protease, the approach used was one that had been developed for renin inhibitors. HIV protease cleaves the linkage between two amino acids — phenylalanine (Structure 4.3) and proline (Structure 4.4). 

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