ABSTRACT
Angiotensin II and endothelin-1 activate their respective AT(1) and ET(A) receptors on vascular smooth muscle cells, producing vasoconstriction, and both peptides are implicated in the pathogenesis of essential hypertension. Angiotensin II potentiates the production of endothelin, and conversely endothelin augments the synthesis of angiotensin II. Both AT(1) and ET(A) receptor antagonists lower blood pressure in hypertensive patients; thus, a combination AT(1)/ET(A) receptor antagonist may have greater efficacy and broader utility compared with each drug alone. By rational drug design a biphenyl ET(A) receptor blocker was modified to acquire AT(1) receptor antagonism. These compounds (C and D) decreased Sar-Ile-Angiotensin II binding to AT(1) receptors and endothelin-1 binding to ET(A) receptors, and compound C inhibited angiotensin II- and endothelin-1-mediated Ca(2+) transients. In rats compounds C and D reduced blood pressure elevations caused by intravenous infusion of angiotensin II or big endothelin-1. Compound C decreased blood pressure in Na(+)-depleted spontaneously hypertensive rats and in rats with mineralocorticoid hypertension. Compound D was more efficacious than AT(1) receptor antagonists at reducing blood pressure in spontaneously hypertensive rats, and its superiority was likely due to its partial blockade of ET(A) receptors. Therefore compounds C and D are novel agents for treating a broad spectrum of patients with essential hypertension and other cardiovascular diseases.
Subject(s)
Antihypertensive Agents/therapeutic use , Biphenyl Compounds/therapeutic use , Blood Pressure/drug effects , Hypertension/drug therapy , Oxazoles/therapeutic use , Receptor, Angiotensin, Type 1/metabolism , Receptor, Endothelin A/metabolism , Sulfonamides/therapeutic use , Angiotensin II Type 1 Receptor Blockers , Animals , Antihypertensive Agents/pharmacology , Biphenyl Compounds/pharmacology , Calcium/metabolism , Desoxycorticosterone , Disease Models, Animal , Endothelin A Receptor Antagonists , Humans , Irbesartan , Losartan/therapeutic use , Male , Oxazoles/pharmacology , Rats , Rats, Inbred SHR , Sodium/metabolism , Sulfonamides/pharmacology , Tetrazoles/pharmacology , Tetrazoles/therapeutic useABSTRACT
Novel pyrazolopyridopyridazine derivatives have been prepared as potent and selective PDE5 inhibitors. Compound 6 has been identified as a more potent and selective PDE5 inhibitor than sildenafil (1). It is as efficacious as sildenafil in in vitro and in vivo PDE5 inhibition models, and it is orally bioavailable in rats and dogs. The superior isozyme selectivity of 6 is expected to exert less adverse effects in humans when used for erectile dysfunction treatment.
