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  • Review Article
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Aliskiren: the first renin inhibitor for clinical treatment

Nature Reviews Drug Discovery volume 7, pages 399–410 (2008)Cite this article

Key Points

  • The first evidence of the existence of renin was presented by Tigerstedt over 100 years ago. However, the importance of renin and the renin–angiotensin system (RAS) in the pathogenesis of cardiovascular disease was only fully realized in the 1970s.

  • Although the preferred target in the RAS was renin, at the top of the cascade, it was another 20 years before the first inhibitors of renin were available for clinical research.

  • The discovery and development of aliskiren (Tekturna) led to it becoming the first orally active renin inhibitor to be approved for clinical use. It was granted approval for the treatment of hypertension by the US Food and Drug Administration and the European Medicines Agency in 2007.

  • Aliskiren has shown efficacy as a monotherapy. Owing to its long duration of action, aliskiren has been shown to reduce daytime and night-time blood pressure (BP), and its effects last up to 4 weeks after therapy is stopped.

  • Combining aliskiren with other antihypertensive drugs, such as low-and high-dose angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium-channel blockers and diuretics, results in a greater therapeutic efficacy, without adverse drug interactions being observed.

  • Aliskiren has been shown to be safe and efficacious in various patient populations including the elderly, different racial groups, diabetic patients, obese patients and patients with reduced renal and hepatic function.

  • Aliskiren shows potential for end-organ protection on top of standard therapy with ACE inhibitors and ARBs in patients with diabetic kidney disease and in patients with heart failure. When aliskiren is added to standard therapy there is a further positive therapeutic effect on surrogate markers of kidney and heart disease.

  • Renin inhibition opens up new therapeutic potential for more complete blockade of the RAS and further decreases in cardiovascular morbidity and mortality.

Abstract

The first evidence of the existence of renin was presented over 100 years ago. However, the importance of renin and the renin–angiotensin system in the pathogenesis of cardiovascular disease was only fully realized in the 1970s. It was another 20 years before the first inhibitors of renin were available for clinical research. Here, we describe the discovery and development of aliskiren, an orally active renin inhibitor, which became the first drug in its class to receive regulatory approval. In 2007, it was approved for the treatment of hypertension by the US Food and Drug Administration and the European Medicines Agency.

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Figure 1: Aliskiren: from bench to marketplace.
Figure 2: Schematic of the renin–angiotensin system (RAS).
Figure 3: Renin inhibitors.
Figure 4: The synthon approach to produce aliskiren at an acceptable cost-of-goods.
Figure 5: Clinical pharmacology of aliskiren.
Figure 6: Aliskiren as a monotherapy.
Figure 7: Combination of aliskiren with other antihypertensives.
Figure 8: Aliskiren and end-organ protection.

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Authors and Affiliations

  1. Speedel, Hirschgässlein 11, Basel, 4051, CH, Switzerland

    Chris Jensen, Peter Herold & Hans Rudolf Brunner

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  1. Chris Jensen
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  2. Peter Herold
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Correspondence to Chris Jensen.

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Competing interests

Chris Jensen is a consultant to Speedel Holding Ltd and a shareholder. He is also a former employee of Speedel Experimenta Ltd, Basel, Switzerland.

Peter Herold is employed by Speedel Experimenta Ltd.

Hans Rudolf Brunner is a consultant to Speedel Holding ltd and a shareholder.

Supplementary information

Supplementary information S1 (table)

Change from baseline to endpoint in mean sitting diastolic (DBP) and systolic blood (SBP) pressure in five placebo-controlled studies, ITT population1–5. (PDF 161 kb)

Glossary

Hypertrophy

An increase in ventricular mass, which is typically characterized by an increased cardiac myocyte size in conjunction with cardiac fibrosis.

Fibrosis

The formation of excess connective tissue.

Angioedema

A rapid swelling of the skin, mucosa or submucosal tissues.

Diuretics

Drugs that increase the net renal excretion of solute and water.

Peptidomimetic

Small-molecule chemicals that mimic the effects of short peptides.

Chiral centre

Any atom in a molecule bearing at least four different substituents.

Synthon

A synthon is defined as a structural unit within a molecule that is related to a possible synthetic operation.

Proteinuria

The presence of excess serum proteins in the urine.

Aldosterone

A steroid hormone that acts to reabsorb sodium and increases blood pressure.

Retrosynthetic analysis

A synthesis that is planned in reverse, beginning with the final product.

Cytochrome P450 system

A family of haem proteins responsible for oxidative drug metabolism.

BNP

Brain natiuretic protein is secreted by the heart in response to stretching of the heart muscle cells. It is used as a biochemical measure of heart failure.

Macro-albuminuria

The urinary excretion of >300 mg per day of serum albumin.

Urinary albumin creatinine ratio

A biochemical measure of chronic kidney disease.

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Jensen, C., Herold, P. & Brunner, H. Aliskiren: the first renin inhibitor for clinical treatment. Nat Rev Drug Discov 7, 399–410 (2008). https://doi.org/10.1038/nrd2550

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