[6] These drugs inhibit the first and rate-limiting step of the renin–angiotensin–aldosterone system (RAAS), namely the conversion of angiotensinogen to angiotensin I.

These compounds were nonpeptidic renin inhibitors, had acceptable oral bioavailability and were potent enough for clinical use.

In 1896, the Finnish physiologist Robert Tigerstedt and the Swedish physician Per Bergman did an experiment on kidneys and the circulatory system in rabbits.

They observed that blood pressure rose in the rabbits when extracts of the kidneys were injected into their jugular veins.

[9][10] They also discovered this substance responsible for higher blood pressure was produced in the renal cortex, and they named it renin.

[10] Although this experiment laid the foundation for future investigations into the RAAS pathway, it had little impact on the scientific community at that time.

[7] Pepstatin, which was described in 1972, was the first synthetic renin inhibitor, but poor pharmacokinetic properties prevented it from entering in vivo investigations.

[15] In 2007, aliskiren was approved by the US Food and Drug Administration and the European Medicines Agency as a treatment for hypertension.

[7] A systematic review by the Cochrane Hypertension group found the maximum recommended dose of aliskiren produced an appreciable decline in blood pressure over placebo.

[21] Ang II stimulates renal sodium retention; promotes aldosterone secretion; causes vasoconstriction, and increases sympathetic nervous system activity.

[20][23] Ang II also provides a negative feedback to the system by inhibiting renin release by the juxtaglomerular apparatus.

[23] The net effect is to increase blood pressure, which in normal physiology is necessary in order to maintain homeostasis.

It is suspected that essential hypertension, a heterogeneous disorder whose long-term effects can be end organ damage, can involve at least in some cases an overactivity of this system, which several types of medications attempt to counter.

This can be problematic for ACE inhibitor and angiotensin II receptor antagonist therapy since increased PRA could partially overcome the pharmacologic inhibition of the RAAS cascade.

[31][32] Statine, an amino acid, is thought to be responsible for the inhibitory activity of pepstatin, because it mimics the tetrahedral transition state of the peptide catalysis.

[13][36][37] The drugs in the latter group seemed to be effective in inhibiting renin activity and lowering blood pressure in both animals and humans.

They also turned out to have short durations of action, low potencies and their ability to lower blood pressure was inadequate.

[7][22][28] Aliskiren, an orally active non-peptide renin inhibitor, was the first drug in its class on the market.

Now, a solution has been found to the problem that impeded the development of the renin inhibitors of the previous generations.

This led to the design of small molecules, non-peptide inhibitors, which were very potent and specific of human renin.

[22][40] However, caused by their chemical structure even third-generation renin inhibitors are difficult to resorb by the human body and their oral bioavailability is often below 2%.

[42] A flexible flap made from amino acids formed in a β-hairpin closes the active site by covering the cleft.

These ligands can be structurally diverse and form van der Waals bonds to the surface of the superpocket.

[46] The side chain of aliskiren binds the S3sp subpocket ideally, and leads to its quality as an inhibitor of human renin.

They advised that such drug combinations should not be used in patients with diabetes because of the risk of causing renal impairment, hypotension, and hyperkalemia and that aliskiren should not be used with ARBs or ACE inhibitors in patients with moderate to severe renal impairment (i.e., where glomerular filtration rate [GFR] < 60 mL/min).

The results showed it was safe and well tolerated over a four-week period, and it reduced blood pressure by 9.8 to 17.9 mmHg.