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Biomedical subjects

J L Archibald

Publications and source records attributed to J L Archibald.

10 recordsLinked to original sources
PubMed1990

Design of an antithrombotic-antihypertensive agent (Wy 27569). Synthesis and evaluation of a series of 2-heteroaryl-substituted dihydropyridines.

An approach to the design of potential combined antithrombotic-antihypertensive agents is described. A series of 1,4-dihydropyridines bearing a 1H-imidazol-1-yl or pyrid-3-yl substituted side chain in the 2-position were synthesized and tested for antihypertensive activity in spontaneously hypertensive rats and for inhibition of TXA2 synthetase in rabbit platelets, in vitro. 1,4-Dihydro-2-(1H-imidazol-1-ylmethyl)-6-methyl- 4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester (1) was shown to be similar in potency to nitrendipine as an antihypertensive agent. Compound 1 inhibited TXA2 synthetase in rabbit and human platelets in vitro and reduced plasma TXB2 levels in rats at antihypertensive dose levels. The reductions in thromboxane production observed in vivo and in vitro were accompanied by enhanced levels of 6-KPGF1 alpha, reflecting diversion of the arachidonic acid cascade toward prostacyclin synthesis.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Recent developments in the pharmacology and pharmacokinetics of indoramin.

Some recent studies complementing earlier reports on the pharmacology and pharmacokinetics of indoramin are briefly reviewed. Competitive blockade of peripheral postsynaptic alpha 1-adrenoceptors is confirmed as the primary mechanism for the antihypertensive activity of indoramin. Various reasons have been proposed to explain the absence of reflex tachycardia when blood pressure is reduced by indoramin. These have included myocardial membrane stabilization and selectivity for alpha 1-adrenoceptors. More recently, class III antiarrhythmic activity and a reduction in baroreceptor sensitivity have also been proposed, and several animal studies have indicated that a central cardioregulatory mechanism contributes to the lack of reflex tachycardia. Chronic dosing with indoramin in hypercholesterolemic monkeys significantly raises high-density lipoprotein cholesterol levels. Recent pharmacokinetic and biotransformation studies confirm earlier reports that the drug is well absorbed and extensively metabolized and has a plasma half-life of approximately 5 h. This is increased in the elderly. 6-Hydroxyindoramin is a major metabolite; it is pharmacologically very similar to indoramin itself, except that it penetrates the central nervous system less readily. Plasma levels of this metabolite are about one-third those of indoramin during chronic twice-daily dosing. Its formation is not expected to have any undesirable clinical consequences.

Administration, Oral↗
PubMed1983

Indoramin in the treatment of hypertension. A mini-review and update.

The origins, preclinical development and clinical pharmacology of a new antihypertensive agent, indoramin (Baratol; Wyeth), are briefly reviewed. Indoramin is a competitive postsynaptic alpha-adrenoceptor antagonist with a myocardial membrane-stabilizing component of action. These features are believed to be responsible for its antihypertensive efficacy. They may also explain the absence of problems common to older alpha-blockers such as reflex tachycardia and postural hypotension. Clinical evaluation of a new agent such as indoramin in the management of hypertension is discussed in terms of efficacy, dosage regimen, tolerance, adverse effects, interactions, withdrawal syndrome, and long-term influence on the complications of high blood pressure.

Animals↗
PubMed1980

Antihypertensive ureidopiperidines.

The synthesis of a series of 1-aralkyl-4-ureidopiperidines is reported. These compounds are related to the benzamidopiperidines exemplified by indoramin. Some of the ureidopiperidines are more potent antihypertensive agents than their benzamidopiperidine counterparts. Two examples, 1-(2-thenoyl)-3-[1-[2-(3-indolyl)ethyl]piperid-4-yl]urea and 1-(2-thenoyl)-3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperid-4-yl]urea (19 and 58), emerged as the most potent antihypertensive agents in this series.

Animals↗