ABSTRACT
A potent, bioavailable ACAT inhibitor may have beneficial effects in the treatment of atherosclerosis by (i) reducing the absorption of dietary cholesterol, (ii) reducing the secretion of very low density lipoproteins into plasma from the liver, and (iii) preventing the transformation of arterial macrophages into foam cells. We have found that a mevalonate derivative 2, which contains a 4,5-diphenyl-1H-imidazol-2-yl moiety, inhibits rat hepatic microsomal ACAT in vitro and produces a significant hypocholesterolemic effect in the cholesterol-fed rat. Structure-activity relationships for analogues of 2 demonstrate that the 4,5-diphenyl-1H-imidazole moiety is a pharmacophore for inhibition of rat microsomal ACAT.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Imidazoles/chemical synthesis , Sterol O-Acyltransferase/antagonists & inhibitors , Animals , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Some (+)-11-deoxy-16-phenoxyprostaglandin E1 analogues have been evaluated as uterine stimulants in the anaesthetised pregnant rat. Gastrointestinal side effects, assessed by the antagonism of morphine-induced constipation in the mouse, were relatively low with some of these compounds, six of which had a much more favourable relative selectivity than 16,16-dimethyl-PGE2 methyl ester.
Subject(s)
Alprostadil/analogs & derivatives , Prostaglandins E, Synthetic/pharmacology , Uterus/drug effects , Animals , Digestive System/drug effects , Female , Male , Mice , Morphine/pharmacology , Pregnancy , Rats , Rats, Inbred StrainsSubject(s)
Alprostadil/analogs & derivatives , Prostaglandins E, Synthetic/chemical synthesis , Stomach Ulcer/prevention & control , Animals , Indomethacin/adverse effects , Magnetic Resonance Spectroscopy , Prostaglandins E, Synthetic/therapeutic use , Rats , Rats, Inbred Strains , Stomach Ulcer/chemically induced , Structure-Activity RelationshipABSTRACT
Rat uterine stimulant activity has been determined in vivo for a series of (+)-11-deoxyprostaglandins. The most active members of the series. 11-deoxy-15 methyl-PGE1, 11-deoxy-16,16-dimethyl - PGE1 and its 1-alcohol were 2-3 times more potent than PGE1. Gastrointestinal side effects assessed by the antagonism of morphine-induced constipation in the mouse, were generally relatively low with these compounds and consequently several members of the series had a more favourable relative selectivity than 16,16-dimethyl-PGE2 methyl ester.
Subject(s)
Prostaglandins, Synthetic/pharmacology , Uterine Contraction/drug effects , Animals , Constipation/chemically induced , Cricetinae , Female , Gastrointestinal Motility/drug effects , Luteolytic Agents , Male , Mice , Morphine/antagonists & inhibitors , Prostaglandins, Synthetic/chemical synthesis , Rats , Rats, Inbred StrainsABSTRACT
Some omega-chain phenyl- and 16-phenoxy- analogues of (+/-)-11-deoxyprostaglandin F1 alpha have been synthesized and evaluated for anti-fertility activity in the hamster. 11-Deoxy-16-phenoxy-17,18,19,20-tetranor-PGF1 alpha was the most active member of the series with an ED50 equal to that of PGF2 alpha. 11-Deoxy-17-phenyl-18,19,20-trinor-PGF1 alpha, which was one third as active as PGF2 alpha, was more potent than the corresponding 16- and 18-phenyl compounds. Aryl ring substitution was found to lower activity, except that with the 16-phenyl compound, p-bromo and m-trifluoromethyl substitution increased the potency. The antifertility activity of the phenoxy compounds, which were poor substrates for 15-hydroxyprostaglandin dehydrogenase, was shown to correlate well with the binding affinity for the bovine corpus luteum PGF2 alpha receptor. Some quantitative structure-activity data supporting this finding are presented.
Subject(s)
Luteolytic Agents , Prostaglandins F, Synthetic/pharmacology , Animals , Cattle , Corpus Luteum/metabolism , Cricetinae , Female , Hydroxyprostaglandin Dehydrogenases/metabolism , In Vitro Techniques , Lung/enzymology , Male , Pregnancy , Prostaglandins F, Synthetic/chemical synthesis , Prostaglandins F, Synthetic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis and gastrointestinal pharmacology of some 11-deoxyprostaglandin E1 analogues are described with results analysed for selectivity from side effects. 11-Deoxygenation reduced potency relative to PGE2 but, as has been reported for natural PGs, 15- or 16-methyl analogues were more potent than the unsubstituted parent compound in the order 16-methyl greater than 15-methyl greater than 16,16-dimethyl. The results suggest that a complex interaction between C-15 and C-16 in methyl analogues affects their profile of activity, but that none of the modifications studied conferred a substantial potency or selectivity advantage over PGE2.
Subject(s)
Digestive System/drug effects , Prostaglandins E, Synthetic/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Constipation/chemically induced , Drug Evaluation, Preclinical , Gastric Juice/metabolism , Indomethacin/antagonists & inhibitors , Male , Mice , Morphine/antagonists & inhibitors , Morphine/pharmacology , Pentagastrin/antagonists & inhibitors , Pentagastrin/pharmacology , Prostaglandins E, Synthetic/pharmacology , Rats , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapyABSTRACT
A series of 1-(2-acyl-4-acylaminophenoxy)-3-isopropylaminopropan-2-ols has been synthesized and examined for beta-receptor blocking and antiarrhythmic activity. Several of these compounds are more than 20 times as active in blocking cardiac beta-receptors than vascular beta-receptors when given intravenously to anesthetized cats. The activities have been correlated quantitatively with partition and steric substitution constants. The observed relationships are consistent with a tentative proposal that the vascular receptor is situated in a more lipophilic environment than the cardiac receptor so that there is a differential transport effect between the two types of receptor.
