Walter Fuhrer

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.

Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin

BACKGROUND The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin. RESULTS Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised. CONCLUSIONS Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.

Effects of a specific and long-acting renin inhibitor in the marmoset.

Inhibition of renin was induced in conscious marmosets with CGP 29 287, Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys (Boc)-OMe, a renin inhibitor with a prolonged duration of action. In vitro, CGP 29 287 is a potent inhibitor of primate plasma renin (inhibitory concentration, 50%: human = 1 X 10(-9) M; marmoset = 5 X 10(-9) M) and less potent against dog (2 X 10(-7) M) or rat (3 X 10(-5) M) plasma renin. CGP 29 287 is a weak inhibitor of other aspartic proteases such as porcine pepsin or bovine cathepsin D (inhibitory concentration, 50% = 4 X 10(-5) M). In furosemide-treated marmosets, CGP 29 287 lowered blood pressure and inhibited plasma renin activity during intravenous infusion and after intravenous bolus injection. The duration of action after intravenous injection was dose dependent and ranged from 1 hour after 0.1 mg/kg to more than 3 hours after 10 mg/kg. High doses of CGP 29 287 (100 mg/kg) were active after oral administration. In all experiments a close relation between inhibition of plasma renin activity and reduction of blood pressure was found. A maximum hypotensive response to CGP 29 287 was associated with complete inhibition of plasma renin activity, and the recovery of blood pressure was accompanied by recovery of plasma renin activity. The hypotensive effects of CGP 29 287 were smaller in untreated than in furosemide-treated marmosets. CGP 29 287 had no influence on blood pressure in marmosets after bilateral nephrectomy or after pretreatment with a converting enzyme inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

BIOACTIVE HYDROXYETHYLENE DIPEPTIDE ISOSTERES WITH HYDROPHOBIC (P3-P1)-MOIETIES. A NOVEL STRATEGY TOWARDS SMALL NON-PEPTIDE RENIN INHIBITORS

Abstract The design and synthesis of new truncated δ-amino hydroxyethylene dipeptide isosteres lacking the P 4 -P 2 peptide backbone is described. The most active compounds 15c and 30c inhibited human renin in the submicromolar range. This promising concept may offer the possibility to discover completely non-peptide, lowmolecular weight renin inhibitors with improved pharmacokinetic properties.