Novel 2,7-Dialkyl-Substituted 5(S)-Amino-4(S)-hydroxy-8-phenyl-octanecarboxamide Transition State Peptidomimetics Are Potent and Orally Active Inhibitors of Human Renin

Abstract

The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2' modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.

Application of 3D QSAR CoMFA/CoMSIA and in silico docking studies on novel renin inhibitors against cardiovascular diseases

“…Furthermore, the yellow colored contours in region A indicate that there is a small available space in the active site for interactions. This is in correlation with previous published reports suggesting that R 2 group interacts with a narrow subsite (S3 sub-pocket) [18,19]. Large yellow colored contours on the region C (Figs.…”

“…The produced QSAR models were further validated by performing a test set prediction using eight new molecules. Table 1 lists all structures used in the training and test sets and their IC 50 values obtained with purified human renin [18,19]. IC 50 values differ up to 230-fold, thus there is a sufficient diversity in the data set in order to construct stable QSAR models.…”

“…Moreover, aliskiren proved to be a highly potent inhibitor of human renin and in contrast to all previous inhibitors, it is much more potent and long acting in vivo after oral administration in sodium-depleted marmosets and in hypertensive patients [17]. Based on these results, Maibaum et al [18,19] expanded the studies on renin inhibitors and synthesized 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamide analogues that can be described as aliskiren derivatives. The thirty reported compounds of this research group [18,19] were used as database for performing three-dimensional quantitative structure-activity relationships (3D QSAR) studies.…”

“…Based on these results, Maibaum et al [18,19] expanded the studies on renin inhibitors and synthesized 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamide analogues that can be described as aliskiren derivatives. The thirty reported compounds of this research group [18,19] were used as database for performing three-dimensional quantitative structure-activity relationships (3D QSAR) studies. To our knowledge the present study is the first application for 3D QSAR on non-peptide renin inhibitors.…”

Tailoring Peptidomimetics for Targeting Protein–Protein Interactions

“…Modifications which enable the classification of type I as peptidomimetics are the ones made at the amide backbone structure (e.g., amide bond isosteres). Type I mimetics have been used as inhibitors for aspartic proteases (74), cysteine protease (75), renin (76,77), and the critical p53/MDM2 interaction present in many cancers (78).…”