Renin inhibitor, hypertension treatment

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. 

Figure 2.5). Aliskiren improves upon the activity of /3-blockers because its use does not cause a dry cough in patients. To date, aliskiren is the only renin inhibitor that has been approved for treatment of hypertension. 

Bio-Mega/Boehringer Ingelheim have used an oxazolidinone auxiliary in the synthesis of renin inhibitors (e.g., 40) for the treatment of hypertension and congestive heart failure.58 A multi-step derivitization of the oxazolidinone 41 from reaction of (6)-4-(l-methylethyl)-2-oxazolidinone and 4-bromo-4-pentenoic acid yielded the desired compound. 

Kempf. D.J. (1994) Design of symmetry-based, peptidomimetic inhibitors of human immunodeHciency virus protease. Methods Enzymol.. 241. 334-354. Wood, J.M. ef al. (1994) Pharmacology of renin inhibitors and their application to the treatment of hypertension. Pharmacol. Ther, 61.325-344. 

The orally active renin inhibitor aliskiren (tekturna) is now available for the treatment of hypertension, in studies to date, it has produced a dose-dependent decrease in blood pressure with few adverse effects. Renin inhibitors will likely provide an attractive alterative to current drugs... 

Renin Inhibitor Aliskiren as Drug for the Treatment of Hypertension... 

An alternative option for the treatment of hypertension was pursued with direct renin inhibitors. [21 ] Monoclonal antibodies, directed against renin, had shown blood pressure lowering properties in animal models. However, due to their immunogenicity and mandatory parenteral administration, they proved not suitable for long term treatment. 

Analysis of the amino acid sequences of PLE isoenzymes revealed that the remarkably small differences of ca. 20 amino acids are not distributed randomly but are located within distinct conserved areas. Among the different isoenzymes, PLE-1 and an isoenzyme termed A-PLE ° [247] were shown to be most useful for stereoselective ester hydrolysis. The latter enzyme, which was expressed at a high level in Pichia pastoris, is remarkably stable and showed perfect enantioselectivity for the resolution of methyl (4 )-5-chloro-2-isopropyl-4-pentenoate, which is a key building block for the synthesis of the renin inhibitor aliskiren, which is used in the treatment of hypertension (Scheme 2.36) [248]. 

Riccioni G, Vitulano N, D Orazio N, Bellocci F. Aliskiren, the first approved renin inhibitor. Clinical application and safety in the treatment of hypertension. Adv Ther 2009 26(7) 700-10. 

Sanoski CA. Aliskiren an oral direct renin inhibitor for the treatment of hypertension. Pharmacotherapy 2009 29(2) 193-212. 

Aliskiren is the most advanced of these and the first to be approved for the treatment of hypertension. In healthy subjects, aliskiren produces a dose-dependent reduction in plasma renin activity and Ang I and II and aldosterone concentrations. In patients with hypertension, many of whom have elevated plasma renin levels, aliskiren suppresses plasma renin activity and causes dose-related reductions in blood pressure similar to those produced by ACE inhibitors (Figure 17-3). The safety and tolerability of aliskiren appear to be comparable to angiotensin antagonists and placebo. 

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