Renin Inhibitors

Renin inhibitors are a group of pharmaceutical drugs used primarily in treatment of hypertension (high blood pressure).

These drugs inhibit the first and rate-limiting step of the renin-angiotensin-aldosterone system (RAAS). Since the 1970s, scientists have been trying to develop potent inhibitors with acceptable oral bioavailability.

Pepstatin, which was described in 1972, was the first synthetic renin inhibitor, but poor pharmacokinetic properties prevented it from entering in vivo investigations. The first generation of renin inhibitors, such as H-142, were peptide analogues of angiotensinogen. However, these inhibitors had also limited drug-like properties. Hopes of breakthrough appeared in 1982 when development of the second generation renin inhibitors began. This generation consisted of peptide-like compounds, such as remikiren, enalkiren and zanikiren. They had more drug-like rather than substrate-like properties, and in 1990 they went to clinical trials. The second generation had its limitations and never completed clinical trials.

Synthesis of Aliskiren

Aliskiren, the only renin inhibitor to go into phase III clinical trials, is not structurally related to peptides, which makes it a third-generation renin inhibitor. The first clinical trial was performed in 2000 in healthy volunteers. In 2007, aliskiren was approved by the US Food and Drug Administration and theEuropean Medicines Agency as a treatment for hypertension.

Aliskiren, third generation non-peptide renin inhibitor

Aliskiren (INN) (trade names Tekturna, U.S.; Rasilez, U.K. and elsewhere) is the first in a class of drugs called direct renin inhibitors. Its current licensed indication isessential (primary) hypertension.

Tekturna, U.S.

Mechanism of Action

Renin is the first enzyme in the renin-angiotensin-aldosterone system which plays a role in blood pressure control. Renin cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following thereby increasing plasma volume and blood pressure.

Site of Action

Aliskiren binds to the S3bp binding pocket of renin, essential for its activity. Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I. Aliskiren is also available as combination therapy with hydrochlorothiazide.

 Rasilez, U.K. and elsewhere

Rasilez, U.K. and elsewhere

Adverse Effects:

  • Angioedema
  • Hyperkalemia (particularly when used with ACE inhibitors in diabetic patients)
  • Hypotension (particularly in volume-depleted patients)
  • Diarrhea and other GI symptoms
  • Headache
  • Dizziness
  • Cough
  • Rash
  • Elevated uric acidgout, and renal stones
  • Rarely: allergic swelling of the face, lips or tongue and difficulty breathing

Tekturna tablet


  • Pregnancy: other drugs such as ACE inhibitors, also acting on the renin-angiotensin system have been associated with fetal malformations and neonatal death
  • Breast feeding: during animal studies, the drug has been found present in milk.

Aliskiren has not yet been evaluated in patients with significantly impaired renal function.

Drug Interactions:

Aliskiren is a minor substrate of CYP3A4 and, more important, P-glycoprotein:

  • Reduces furosemide blood concentration.
  • Atorvastatin may increase blood concentration, however no dose adjustment needed.
  • Possible interaction with ciclosporin (the concomitant use of ciclosporin and aliskiren is contraindicated).
  • Caution should be exercised when aliskiren is administered with ketoconazole or other moderate P-gp inhibitors (itraconazole, clarithromycin, telithromycin, erythromycin, amiodarone).
  • Doctors should stop prescribing aliskiren-containing medicines to patients with diabetes (type 1 or type 2) or with moderate to severe kidney impairment who are also taking an ACE inhibitor or ARB, and should consider alternative antihypertensive treatment as necessary.

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