Jürgen Maibaum

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.

Renin inhibitors as novel treatments for cardiovascular disease

The renin–angiotensin system (RAS) plays an important role in the development of cardiovascular diseases such as hypertension and heart failure. Inhibitors of renin (EC 3.4.99.19) block the RAS at its first and rate-limiting step and may therefore offer major potential benefits in blood pressure control. Despite intensive research, however, previous attempts to develop clinically useful renin inhibitors have failed. This review discusses recent patent applications for the development of two novel classes of non-peptide renin inhibitors: 3-alkoxy-4-aryl-piperidines, such as Ro 66-1132 (Hoffmann-La Roche), and alkanecarboxamides, such as aliskiren (SPP-100; Novartis). Both classes are effective in animal models, while results from studies in humans suggest that aliskiren may represent the first in a new class of orally-effective renin inhibitors. Patents claiming the use of renin inhibitors in combination therapy are also discussed.

A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate

We report a convergent synthesis of the potent orally active non-peptide renin inhibitor CGP60536B. The key reaction employs the coupling of the enantiopure Grignard species derived from chloride 13 with the diastereomerically pure γ-lactone 9b. The stereoselective reduction of the resulting ketone 14b has been thoroughly investigated.

Pharmacology of renin inhibitors and their application to the treatment of hypertension

Several different strategies have been followed to block the activity of renin, the enzyme catalysing the first and rate-limiting step in the renin-angiotensin cascade. The unique substrate specificity of this enzyme makes it an attractive target for specifically interfering with the renin-angiotensin system. Attempts to block the activity of renin in animals by an immunological approach, with either active or passive immunization against renin, have been successful. This approach has not been considered as a realistic therapy in humans for the treatment of hypertension or heart failure, but has provided useful tools for purifying and quantifying renin. Considerable efforts have been focused on the design of orally active, synthetic inhibitors of renin. This has resulted in the discovery of low molecular weight pseudo-tetrapeptide compounds that are resistant to enzymatic cleavage and are potent and selective inhibitors of renin. Studies in animal models and preliminary studies in humans indicate that renin inhibitors have the same therapeutic potential as angiotensin-converting enzyme inhibitors. However, the generally poor oral bioavailability and rapid elimination of currently available renin inhibitors have prevented their development as useful drugs. Inhibitors with better oral bioavailability and a long duration of action are needed to assess their full therapeutic potential and to determine whether they offer advantages over the angiotensin-converting enzyme inhibitors or the more recently developed angiotensin II-receptor antagonists.

Design and synthesis of novel 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides as in vitro potent peptidomimetic inhibitors of human renin

Abstract Novel low-molecular weight transition-state peptidomimetic renin inhibitors characterized by an all-carbon 8-phenyl substituted octanecarboxamide skeleton have been discovered based on a topographical design approach. The in vitro most potent inhibitors 21, 25 and 26 incorporating a strong H-bond acceptor group linked to the benzyl spacer of the (P3-P1)-unit had IC50s in the low nanomolar range against human renin.

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.

Small-molecule factor D inhibitors targeting the alternative complement pathway

Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH). Here we describe the identification of potent and selective small-molecule inhibitors of FD. These inhibitors efficiently block alternative pathway (AP) activation and prevent both C3 deposition onto, and lysis of, PNH erythrocytes. Their oral administration inhibited lipopolysaccharide-induced AP activation in FD-humanized mice. These data demonstrate the feasibility of inhibiting the AP with small-molecule antagonists and support the development of FD inhibitors for the treatment of complement-mediated diseases.

The P1 N-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin

Novel nonpeptide small molecule renin inhibitors bearing an N-isopropyl P(1) motif were designed based on initial lead structures 1 and aliskiren (2). (P(3)-P(1))-Benzamide derivatives such as 9a and 34, as well as the corresponding P(1) basic tertiary amine derivatives 10 and 35 were found to display low nanomolar inhibition against human renin in vitro.

A Novel Class of Oral Direct Renin Inhibitors: Highly Potent 3,5-Disubstituted Piperidines Bearing a Tricyclic P3–P1 Pharmacophore

A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.