Daglutril

Since the discovery of endothelin (ET)‐1 in 1988, the main components of the signalling pathway have become established, comprising three structurally similar endogenous 21‐amino acid peptides,ET‐1,ET‐2 andET‐3, that activate twoGPCRs,ETAandETB. Our aim in this review is to highlight the recent progress inETresearch. TheET‐like domain peptide, corresponding to prepro‐ET‐193–166, has been proposed to be co‐synthesized and released withET‐1, to modulate the actions of the peptide.ET‐1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long‐lasting action. To date, the major therapeutic strategy to block the unwanted actions ofETin disease, principally in pulmonary arterial hypertension, has been to use antagonists that are selective for theETAreceptor (ambrisentan) or that block both receptor subtypes (bosentan). Macitentan represents the next generation of antagonists, being more potent than bosentan, with longer receptor occupancy and it is converted to an active metabolite; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy. A second strategy is now being more widely tested in clinical trials and uses combined inhibitors ofET‐converting enzyme and neutral endopeptidase such asSLV306 (daglutril). A third strategy based on activating theETBreceptor, has led to the renaissance of the modified peptide agonistIRL1620 as a clinical candidate in delivering anti‐tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions. Finally, we discuss biased signalling, epigenetic regulation and targeting with monoclonal antibodies as prospective new areas forETresearch.

There is a persistent need for the development of new antihypertensive drugs, because the control of blood pressure is still not achievable in a significant proportion of hypertensive patients. Since the approval in 2007 of aliskiren, no other new antihypertensive based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons. Despite these difficulties, the pipeline is not dry and different new antihypertensive strategies targeting the renin-angiotensin-aldosterone pathway, are in clinical development stage. The dual angiotensin II receptor-neprilysin inhibitor LCZ696, a single molecule synthetized by cocrystallisation of valsartan and the neprilysin inhibitor prodrug AHU377 is in development for resistant hypertension and for heart failure. Daglutril is a dual neprylisin-endothelin converting enzyme inhibitor which was shown to decrease BP in patients with type 2 diabetic nephropathy. Aldosterone synthase inhibitors and the third and fourth generation non-steroidal dihydropyridine based mineralocorticoid receptors blockers are new ways to target the multiple noxious effects of aldosterone in the kidney, vessels and heart. Centrally acting aminopeptidase A inhibitors block brain angiotensin III formation, one of the main effector peptides of the brain renin angiotensin system. However, a long time will be still necessary to evaluate extensively the efficacy and safety of these new approaches. In the mean time, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension.