Structure-based design of aliskiren, a novel orally effective renin inhibitor

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.