Dual ACE/NEP inhibitors – more than playing the ACE card

Jandeleit‐Dahm, Karin

doi:10.1038/sj.jhh.1002018

Cited by 25 publications

(16 citation statements)

References 29 publications

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“…Further, while ECE inhibitors can be expected to share the adverse teratological effects of ET receptor antagonists, additional tolerability issues may arise from the loss of ancillary ECE‐mediated functions such as bradykinin degradation. Combined ACE/NEP inhibitors have been associated with a high incidence of treatment‐limiting angio‐oedema, an effect attributed to loss of two bradykinin catabolic pathways ( Jandeleit‐Dahm, 2006 ). Given that bradykinin is also a substrate for ECE, ( Hoang and Turner, 1997 ) combined ECE/NEP inhibitor treatment may also be inappropriate for the large proportion of cardiovascular disease patients treated with ACE inhibitors.…”

Section: Strategies For Pharmacological Inhibition Of Et‐1 Activitymentioning

confidence: 99%

The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

Kirkby

Hadoke

Bagnall

et al. 2008

British J Pharmacology

159

152

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There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET A receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.

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Section: Strategies For Pharmacological Inhibition Of Et‐1 Activitymentioning

confidence: 99%

The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

Kirkby

Hadoke

Bagnall

et al. 2008

British J Pharmacology

159

152

View full text Add to dashboard Cite

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“…These findings have provided the impetus to develop inhibitors that simultaneously block angiotensin II and increase ANP, which are regulated by endothelial, membrane-bound ACE and NEP, Fig. (2) 69 . The concept of dual inhibition of the two enzymes by a single molecule has shown major benefits and potential superiority versus other agents in various experimental models of hypertension, heart failure, and renal diseases.…”

Section: Metalloproteasesmentioning

confidence: 99%

Extracellular Proteases as Targets for Drug Development

Čudić¹,

Fields²

2009

CPPS

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Proteases constitute one of the primary targets in drug discovery. In the present review, we focus on extracellular proteases (ECPs) because of their differential expression in many pathophysiological processes, including cancer, cardiovascular conditions, and inflammatory, pulmonary, and periodontal diseases. Many new ECP inhibitors are currently under clinical investigation and a significant increase in new therapies based on protease inhibition can be expected in the coming years. In addition to directly blocking the activity of a targeted protease, one can take advantage of differential expression in disease states to selectively deliver therapeutic or imaging agents. Recent studies in targeted drug development for the metalloproteases (matrix metalloproteinases, adamalysins, pappalysins, neprilysin, angiotensin-converting enzyme, metallocarboxypeptidases, and glutamate carboxypeptidase II), serine proteases (elastase, coagulation factors, tissue/urokinase plasminogen activator system, kallikreins, tryptase, dipeptidyl peptidase IV), cysteine proteases (cathepsin B), and renin system are discussed herein.

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“…Longer-term studies are needed in larger populations including patients of different ethnic backgrounds to confirm the laboratory results and to fully characterize the safety profile of these novel ACE/NEP inhibitors. Clinical data indicates towards need to develop novel dual ACE/NEP inhibitors with better safety profiles (Jandeleit-Dahm, 2006).…”

Section: Combined Ace/nep (Neutral Endopeptidase) Inhibitorsmentioning

confidence: 99%