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Structure-based design of aliskiren, a novel orally effective renin inhibitor
Jeanette M Wood1, Jürgen Maibaum, Joseph Rahuel
1Novartis Institute for Biomedical Research, Klybeckstrasse 220, CH-4002 Basel, Switzerland.
Insights
Researchers developed aliskiren, a novel renin inhibitor, to treat hypertension and cardiovascular diseases. This drug offers improved pharmacokinetic properties for effective blood pressure management.
Area of Science:
- Cardiovascular medicine
- Pharmacology
- Drug discovery
Background:
- Hypertension is a significant risk factor for cardiovascular diseases, including stroke, myocardial infarction, and heart failure.
- Inhibitors of the renin-angiotensin system (RAS) are effective treatments for hypertension.
- Renin, catalyzing the rate-limiting step of the RAS, is an optimal target for inhibition.
Purpose of the Study:
- To design novel renin inhibitors with improved pharmacokinetic properties compared to existing peptide-like compounds.
- To identify a new class of drugs for the treatment of hypertension and associated cardiovascular diseases.
Main Methods:
- Utilized molecular modeling and crystallographic structure analysis to design renin inhibitors.
- Synthesized and tested aliskiren for potency and selectivity against human renin in vitro and in vivo.
- Evaluated the efficacy of aliskiren in lowering blood pressure in animal models and human patients.
Main Results:
- Discovered aliskiren, a potent and selective inhibitor of human renin.
- Demonstrated that once-daily oral doses of aliskiren effectively inhibit renin and reduce blood pressure.
- Observed positive results in sodium-depleted marmosets and hypertensive human patients.
Conclusions:
- Aliskiren is the first in a new class of renin inhibitors.
- Aliskiren exhibits favorable pharmacokinetic properties for potential hypertension treatment.
- This novel drug holds promise for managing hypertension and related cardiovascular conditions.
Abstract:
Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension. As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.