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The optimization of the 4-position of recently described new 3,4-disubstituted piperidine-based renin inhibitors is reported herein. The synthesis and characterization of compounds leading to the discovery of 11 (ACT-178882, MK-1597), a renin inhibitor with a suitable profile for development is described.

The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension.

Background: Pulmonary arterial hypertension (PAH) is a rare condition characterized by elevated pulmonary artery pressure leading to right-heart failure and death. Endothelin (ET)-1 has been shown to play a significant pathogenic role in PAH. ET-3 has not yet been investigated in PAH. Methods: ET-1 and ET-3 plasma concentrations were measured in 33 PAH patients prior to any specific PAH therapy and in 9 control subjects. In PAH patients, hemodynamic parameters measured by right-heart catheterization, 6-min walk distance (6MWD), New York Heart Association (NYHA) functional class, and time until lung transplantation or death were recorded. Results: In patients with PAH, levels of ET-1 were increased while those of ET-3 were decreased, as compared to control subjects (p o 2 ). ET-3 correlated positively with 6MWD. ET-1/ET-3 ratio correlated positively with RAP, negatively with Sv o 2 and 6MWD, and was also associated with NYHA functional class. ET-1/ET-3 ratio was associated with prognosis in this sample of PAH patients treated with specific therapies. Conclusions: PAH is characterized by elevated ET-1 and ET-1/ET-3 ratio and decreased ET-3 plasma concentrations. All of them correlate with hemodynamic and clinical markers of disease severity. ET-1/ET-3 ratio might be a novel prognostic factor in PAH. These preliminary data should be validated in a large prospective multicenter cohort of PAH patients.

Although hypertension affects approximately 1 billion people worldwide, it remains one of the most modifiable risk factors for cardiovascular disease. It is well established that the renin angiotensin aldosterone system (RAAS) plays a major role in the pathophysiology of hypertension and drugs that target this pathways have proven efficacy. It has long been speculated, however, that renin inhibitors may provide more effective suppression of the RAAS. Many of the obstacles associated with the development of early renin inhibitors have been overcome and it is likely that the first renin inhibitors will be available within the next 3 years.

The identification, synthesis and activity of a novel class of piperidine renin inhibitors is presented. The most active compounds show activities in the picomolar range and are among the most potent renin inhibitors ever identified.

Human renin has been expressed in Sf9 and CHO cells using two different gene constructs. The first construct contained a foreign signal peptide fused directly to the sequence encoding mature renin, whereas the second construct harbors the sequence for preprorenin. Prorenin was produced in significantly higher amounts than the mature enzyme expressed without its propeptide in both expression systems. Both directly expressed mature renin and proteolytically derived active renin have been purified and cocrystallized with the renin inhibitor Ro 42-5892. The 3D structure has been solved for both versions and demonstrates identity despite different glycosylation and different N termini.

ACE inhibition has been shown to prevent neointima formation after vascular injury. However, it is not known if this effect is due to a specific inhibition of the renin angiotensin system or to another mechanism such as the accumulation of bradykinin. In order to answer this question we compared the effects of maximal effective doses of cilazapril, an angiotensin converting enzyme (ACE) inhibitor, and ciprokiren, a new renin inhibitor, in guinea pigs. Vascular injury was induced by endothelial denudation of the right carotid artery of guinea pigs treated either by saline (control group), cilazapril (30 mg/kg/day) or ciprokiren (24 mg/kg/day). Twelve days after the ballooning, the guinea pigs were sacrificed, the carotid arteries were perfused fixed and neointima formation was evaluated by quantitative morphometry. Both, ciprokiren and cilazapril prevented neointima formation to the same extent (inhibition by 42 and 49%, respectively, p These results suggest that, in guinea pigs, renin inhibition prevents neointima formation to a similar extent as ACE inhibition. Therefore, ACE inhibitors seem to act in this model by inhibiting the renin angiotensin system and not by other effects such as accumulation of bradykinin.

Objectives . The goal of this study was to investigate the evolution of endothelial dysfunction and plasma renin activity in a rat model of heart failure. Background . Endothelial dysfunction has been demonstrated in heart failure and may play a significant role in this pathophysiologic process. Studies have also suggested a physiologic interaction between the renin-angiotensin system and endothelium-derived relaxing factor. However, the evolution of endothelial dysfunction and plasma renin activity in heart failure has not been studied to date. Methods . Endothelium-dependent and -independent relaxations were studied at 1, 4 and 16 weeks after coronary artery ligation in a rat model of heart failure. Thoracic aortic rings were placed in isolated organ baths and acetylcholine and sodium nitroprusside concentration response curves were generated. Plasma renin activity was assessed at each time point. Results . Aortic rings from rats with heart failure demonstrated no evidence of endothelial dysfunction at week 1, although progressive rightward shifts in the acetylcholine curves and decreasing maximal relaxation over time compared with findings in sham-operated control rats were evident at weeks 4 and 16. The sodium nitroprusside curves were not different between rats with heart failure and sham-operated rats. Plasma renin activity was elevated at week 1 and progressively increased through week 16, even though it correlated poorly with endothelial dysfunction. Conclusions . This study suggests that endothelial dysfunction in heart failure is a progressive time-dependent process that probably plays a minor role early in heart failure. Although plasma renin activity increased significantly in rats with heart failure, it was poorly predictive of endothelial dysfunction.

A highly hydrophobic analogue of angiotensin II AT, [Sar 1 , (2′,3′,4′,5′,6′-Br5)Phe 8 ]AT exhibited strong and persistent specific antagonism against AT, both in vitro and in vivo . This peptide exhibited 32% of the binding affinity of [Sar 1 ]AT towards membranes of bovine adrenal cortex, it was a specific AT antagonist of irreversible character on smooth muscle assays, and it also suppressed for over 120 min at 7.10 −8 M/kg the blood pressure response towards AT in the rat blood pressure assay. This compound harbours therefore the potential of a new class of AT-specific antihypotensive drugs.

Two dynorphins of 24 and 32 residues, respectively, were isolated from porcine pituitary and sequenced. They both contain the dynorphin heptadecapeptide, now designated dynorphin A, at the amino terminus, followed immediately by the putative processing signal Lys-Arg. In the 24-residue peptide the subsequent five amino acids comprise the [Leu] enkephalin sequence. In the 32-residue peptide this [Leu] enkephalin sequence is part of a novel opioid tridecapeptide designated dynorphin B.