Renin Inhibition

Renin is the critical enzyme at the beginning of the biochemical cascade that produces the peptide hormone angiotensin II. Inhibitors of the cascade are already very important drugs for treating cardiovascular and kidney disease. Inhibitors of renin are expected to provide more complete and more specific inhibition of this biochemical cascade, with better efficacy and tolerability compared to existing therapies. While major pharmaceutical companies have succeeded in finding prototypical renin inhibitors, all have suffered from the same critical disadvantage: only a small fraction of the drug was absorbed after oral administration. As these were large complicated molecules, also expensive to make, the poor oral bioavailability proved to be a fatal flaw. Most major pharmaceutical companies abandoned their efforts in this field in the mid-1990s.

Actelion has taken a new approach. Rather than continuing to try to make new derivatives of the known potent, large and complicated renin inhibitors, work began on smaller molecules, with good oral absorption, but weak renin inhibitor activity. After several years of chemical optimization work, the Actelion research team has now arrived at potent, orally active renin inhibitors, with high oral bioavailability. The Actelion renin inhibitors have been protected by at least 15 priority patent applications.

Renin inhibitors that act at the beginning of the renin-angiotensin system, are expected to provide more complete and more specific inhibition of the biochemical cascade than other inhibitors targeting the angiotensin-converting enzyme (ACE) or the AT1 receptor.

Urotensin-II

At Actelion, we are pioneering the development of urotensin receptor antagonists for the treatment of certain cardiovascular and metabolic diseases. Urotensin-II is a peptide hormone that is extremely potent in constricting certain blood vessels. It also exerts other long-term adverse effects on several target organs. The urotensin receptor antagonist has passed all hurdles for human clinical studies, which are now in progress. To the best of our knowledge, it remains the most advanced compound of this exciting new therapeutic class.

Endothelin

A major focus of Actelion's research is the endothelium - an organ of fundamental importance that comprises the inner lining of blood vessels. It is the target of many hormones and also produces very potent biomolecules such as endothelin. The receptors for endothelin are the molecular targets of Actelion's Tracleer® (bosentan) and Veletri™ (tezosentan).

Under normal conditions, the endothelium protects against the adhesion of cells or vasoconstriction. In diseased states, however, it leads to abnormal adhesion of cells, inflammation, vascular proliferation and vasoconstriction. Thus, endothelium research may lead to drugs with a wide spectrum of clinical applications.