Renininhibitor

Renin inhibitors, also known as renin inhibitors, are chemical compounds which inhibit the enzyme renin as inhibitors and thus engage regulating the renin-angiotensin -aldosterone system to the blood pressure. They are being developed as potential drugs for the treatment of high blood pressure. The only authorized representative of this group is aliskiren, not yet listed are Zankiren and Remikiren.

History

The first renin inhibitors were antibodies that were directed against the enzyme. This showed in animal experiments already a hypotensive effect. Due to the unfavorable pharmacokinetic properties of antibodies, which only allow a bet via an injection, these antibodies have not been developed. With pepstatin, a protease inhibitor from actinomycetes, a first low molecular weight renin inhibitor could be found. This peptidic renin inhibitor was also effective only after parenteral administration. Optimization of the structural motif of renin inhibitors pepstatin led to the first generation, which include for example Zankiren, Remikiren and Enalkiren belong. These peptidomimetics have failed in the early phases of clinical development due to poor oral bioavailability. This issue has been resolved sufficiently in the case of aliskiren. Therefore Aliskiren was approved in 2007 as the first renin inhibitor for the treatment of high blood pressure.

Pharmacology

Pharmacodynamics ( mechanism of action )

Renin inhibitors inhibit by binding to the catalytic center of the protease renin converting angiotensinogen to angiotensin I, which are precursors of the pressor angiotensin II. In this way, access renin inhibitors very early in the renin -angiotensin -aldosterone system, and the production of angiotensin II can be suppressed completely. Thus, renin inhibitors differ from the therapeutically more frequently used ACE inhibitors, which thus only lead of angiotensin I into angiotensin II converting angiotensin converting enzyme, but not inhibit the alternative enzyme chymase, and to an incomplete inhibition of the renin -angiotensin -aldosterone system. In renin inhibitors do not inhibit the degradation of the inflammation mediator, bradykinin, which is a characteristic side effect of the ACE inhibitors, the so-called Kininhusten responsible. A based on the pharmacological properties expected therapeutic superiority over ACE inhibitors is not clinically proven.

Pharmacokinetics

Structurally related renin inhibitors are often problematic pharmacokinetic drugs. They are poorly absorbed and its oral bioavailability is often less than 2%.

Drugs

Renin inhibitors that are in clinical development or were or were drug approval, include:

• Aliskiren
• CGP 38560
• Ciprokiren
• Enalkiren
• Remikiren
• Zankiren