Discovery of remikiren as the first orally active renin inhibitor.

Angiotensin converting enzyme (ACE) inhibitors are used for the treatment of hypertension and congestive heart failure. However, ACE not only cleaves angiotensin I but is also responsible for the degradation of bradykinin. Therefore, renin inhibitors which block the system at an early step without influence on bradykinin should be devoid of side effects. Since renin has a very strong species specificity, it was necessary to develop new techniques to measure arterial pressure as well as hypertension models in primates in order to select orally active renin inhibitors. Remikiren (Ro 42-5892, CAS 126371-83-3) is a very potent renin inhibitor in vitro (IC50 for human renin = 0.7 nmol/l) and in vivo. Despite short lasting biochemical changes the arterial blood pressure decrease induced by remikiren is very long lasting (over 24 h). Several in vivo experiments have shown that remikiren is specific for renin and does not decrease arterial pressure by an unrelated mechanism. In sodium depleted monkeys, the blood pressure decrease induced by remikiren was similar to the blood pressure decrease induced by cilazapril, an ACE inhibitor. Clinical results seem to confirm the preclinical findings and show that remikiren is indeed a potent orally active renin inhibitor inducing a long lasting blood pressure decrease.