Although UII appears to play only a minor role in health, evidence is accumulating that it is involved in cardiovascular and other diseases. In particular, it has been reported that plasma UII levels are increased in hypertension, heart failure, atherosclerosis, diabetes mellitus, and renal failure. For this reason, the development of UII receptor antagonists is of considerable interest. Urantide (“urotensin antagonist peptide”) is a penicillaminesubstituted derivative of UII. Palosuran is an orally active non-peptide antagonist of the UII receptor. It has displayed beneficial effects in animal models of renal failure but not in hypertensive patients with type 2 diabetic nephropathy. More potent UII antagonists are available. GSK1440115 has undergone phase 1 testing for the treatment of asthma but was found to be ineffective. Thus, the role of UII in disease remains to be defined.
Selective competitive antagonist of • Eprosartan, irbesartan, candesartan, olmesartan, telmisartan: Similar to valsartan •IcatibantSelective antagonist of kinin B2 receptors Blocks effects of kinins on pain, hyperalgesia, and inflammation Hereditary angioedema •Cinryze, Berinert: Plasma C1 esterase inhibitors, decrease bradykinin formation, used in hereditary angioedema •Ecallantide: Plasma kallikrein inhibitor
Agonist of vasopressin V1 (and V2) receptors • Selepressin, terlipressin: More selective for V1a receptor
Antagonist of vasopressin V1 and V2 receptors
Relcovaptan, SRX251: Increased selectivity for V1 receptor
Tolvaptan: Increased selectivity for V2 receptor
NATRIURETIC PEPTIDES •Nesiritide,CarperitideAgonists of natriuretic peptide receptors Increasedsodiumandwaterexcretion•vasodilationHeart failure •Ularitide: Synthetic form of urodilatin
Decreases metabolism of natriuretic peptides and formation of angiotensin II • Sampatrilat, fasidotrilat: Similar to omapatrilat •Bosentan,macitentanNonselective antagonists of endothelin ETA and ETB receptors Vasodilation Pulmonary arterial hypertension •Sitaxsentan, ambrisentan: Selective antagonists for ETA receptors
Blocks vasoconstrictor response to neurotensin Potential antiobesity agent
NEUROTENSIN ANTAGONISTS •MeclinertantAntagonist of central and peripheral neurotensin receptors Blocks some central and peripheral (vasodilator) actions of neurotensin None identified CALCITONIN GENE-RELATED PEPTIDE ANTAGONISTS •Telcagepant,olcegepant Antagonists of the calcitonin gene-related peptide (CGRP) receptor Blocks some central and peripheral (vasodilator) actions of CGRP Migraine1 NEUROPEPTIDE Y ANTAGONISTS •BIBP3226Selective antagonist of neuropeptide Y1 receptors Subclass, Drug Mechanism of Action Effects Clinical Applications
BIIE0246: Selective for Y2 receptor
MK-0557: Selective for Y5 receptor 1Undergoing preclinical or clinical evaluation.
Epoprostenol Flolan, Veletri
Balakumar P, Jagadeesh G: Cardiovascular and renal pathologic implications of prorenin, renin, and the (pro)renin receptor: Promising young players from the old renin-angiotensin-aldosterone system. J Cardiovasc Pharmacol 2010;56:570.