Drugs online research references
J Med Chem. 1987 Jan;30(1):49-57.
2,4-diamino-6,7-dimethoxyquinazolines. 1. 2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1-yl] derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.
Campbell SF, Davey MJ, Hardstone JD, Lewis BN, Palmer MJ.
A series of 4-amino-2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1 -yl]-6, 7-dimethoxyquinazoline derivatives was synthesized for evaluation as alpha-antagonists and antihypertensive agents. Most compounds displayed high (nM) binding affinity for alpha 1-adrenoceptors with no significant activity at alpha 2-sites. Selective antagonism of the alpha 1-mediated vasoconstrictor effects of norepinephrine is also characteristic of the series. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented, and structural similarity between the 2,4-diamino-6,7-dimethoxyquinazoline nucleus and norepinephrine is established. An alpha 1-receptor model is presented in which charge-reinforced hydrogen bonding is important for binding of both antagonist and agonist molecules. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and several compounds displayed similar efficacy to prazosin when assessed after 6 h. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compound 1 (doxazosin) was selected for further evaluation and is currently progressing through phase III clinical trials.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2879919&dopt=Abstract
Am J Cardiol. 1987 May 29;59(14):29G-34G.
Effects of doxazosin on diet-induced hypercholesterolemia in C57BR/cdJ mice.
Swindell AC, Valentine JJ.
Plasma cholesterol levels are markedly reduced when doxazosin, a selective alpha 1-adrenoceptor inhibitor, is administered for several days to C57BR/cdJ mice that have been fed a high cholesterol diet. This system affords a useful model for investigating the mechanism by which selective alpha 1-adrenoceptor inhibitors decrease circulating lipid levels. The results indirectly suggest that hypercholesterolemia induced by dietary cholesterol may involve activation of the sympathetic nervous system. The basis for linkage between circulating cholesterol levels and sympathetic nervous activity, while not yet understood, may involve changes in the balance among cholesterol pathways in the liver, alteration of vasomotor tone and control of the activity of vascular endothelial lipases. An additive effect is described for cholestyramine and doxazosin, in which low density lipoprotein cholesterol is decreased by 76% by a combination of maximal doses of the 2 agents.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2884850&dopt=Abstract
Am J Cardiol. 1987 May 29;59(14):78G-81G.
Pharmacokinetic overview of doxazosin.
Elliott HL, Meredith PA, Reid JL.
After both oral and intravenous administration, doxazosin is extensively metabolized, with only about 5% of the administered dose excreted unchanged in urine. For single doses, oral bioavailability has been calculated to be about 65%; terminal elimination half-life is approximately 10 to 12 hours. In later multiple-dose studies in which doxazosin concentrations were measured beyond 24 hours after administration, the terminal elimination half-life was 22 hours. Clearance of doxazosin, presumably in the liver, involves the production of mainly O-demethylated and C-hydroxylated metabolites, and is low in comparison with hepatic blood flow. Protein binding is reported to be 98.3% in humans. Relatively low clearance (1.0 to 2.0 ml/min/kg) in association with a moderate volume of distribution (1.0 to 1.9 liters/kg) is responsible for doxazosin's relatively long plasma half-life. There is no evidence to suggest that active metabolites contribute significantly to the pharmacologic activity of doxazosin; both hypotensive effect and alpha-adrenoceptor inhibitor activity have been directly related to the concentration of doxazosin in blood. During long-term treatment, no significant changes in the disposition of doxazosin have been reported; with dosages up to the maximum clinically used dosage of 16 mg daily, there is no evidence of dose-dependent pharmacokinetics. Studies in elderly patients have shown no major pharmacokinetic differences. Overall, these pharmacokinetic results suggest that doxazosin is suitable for once-daily administration in the long-term treatment of patients with essential hypertension.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2884857&dopt=Abstract
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