Renin inhibitor

from Wikipedia, the free encyclopedia

Renin inhibitors , also known as renin inhibitors , are chemical compounds which, as inhibitors, inhibit the enzyme renin and thus intervene in the renin-angiotensin-aldosterone system that regulates blood pressure . They are being developed as potential drugs to treat high blood pressure . The only authorized representatives of this group is aliskiren , are not yet listed Zankiren and remikiren .

history

The first renin inhibitors were antibodies that were directed against the enzyme. These have already shown a blood pressure lowering effect in animal experiments . Due to the unfavorable pharmacokinetic properties of antibodies, which only allow use via injection , these antibodies have not been further developed. With pepstatin , a protease inhibitor from actinomycetes , a first low molecular weight renin inhibitor could be found. This peptide renin inhibitor was also effective only after parenteral administration. Optimizations of the structural motif of pepstatin led to the renin inhibitors of the first generation, which include zankiren , remikiren and enalkiren , for example . These peptidomimetics failed in the early stages of clinical development because of poor oral bioavailability . This problem has been adequately resolved in the case of Aliskiren. Therefore, in 2007, aliskiren was approved as the first renin inhibitor for the treatment of high blood pressure.

pharmacology

Pharmacodynamics (mechanism of action)

By binding to the catalytic center of the protease renin, renin inhibitors inhibit the conversion of angiotensinogen into angiotensin I , which are precursors of angiotensin II , which increases blood pressure . In this way, renin inhibitors intervene in the renin-angiotensin-aldosterone system very early, and the production of angiotensin II can be completely stopped. Renin inhibitors thus differ from the therapeutically more frequently used ACE inhibitors , which only inhibit the angiotensin converting enzyme that converts angiotensin I into angiotensin II, but not the alternative enzyme chymase , and thus lead to an incomplete inhibition of the renin-angiotensin-aldosterone system. Furthermore, renin inhibitors do not inhibit the breakdown of the inflammatory mediator bradykinin , which is responsible for a characteristic side effect of ACE inhibitors, the so-called kinin cough. However, a therapeutic superiority over ACE inhibitors to be expected based on the pharmacological properties has not been clinically proven.

Pharmacokinetics

For structural reasons, renin inhibitors are often pharmacokinetically problematic drugs. They are poorly absorbed and their oral bioavailability is often less than 2%.

Medicinal substances

Examples of renin inhibitors that are or have been in clinical development or have been approved for medicinal products include:

literature

Individual evidence

  1. ↑ Wakerlin GE: Antibodies to renin as proof of the pathogenesis of sustained renal hypertension . In: Circulation . 17, 1953, pp. 653-657.
  2. ↑ Deodar SD, Haas E, Goldblatt H: Production of antirenin to homologous renin and its effect on experimental renal hypertension. . In: J. Med.. . 119, March 1964, pp. 425-432. PMID 14129713 . PMC 2137885 (free full text).
  3. ↑ Umezawa H, Aoyagi T, Morishima H, Matsuzaki M, Hamada M: Pepstatin, a new pepsin inhibitor produced by Actinomycetes . In: J Antibiot . 23, No. 5, May 1970, pp. 259-262. PMID 4912600 .