Pharmacology of enoximone.

Enoximone is a new cardiotonic agent, active by both intravenous and oral routes of administration, that is being studied clinically for the treatment of patients with congestive heart failure. The animal pharmacology pertinent to the clinical development of enoximone is reviewed. Direct positive inotropic, positive chronotropic and vasodilator properties have been demonstrated for enoximone in several in vivo and in vitro preparations. However, positive inotropism and vasodilation are the principal effects of this agent with the inotropic effect being the most prominent. In anesthetized dogs, the cardiovascular effects produced by enoximone (0.1 to 1 mg/kg) were not accompanied by significant alterations in myocardial oxygen consumption. Cardiac function was improved by enoximone in anesthetized dogs given myocardial depressant amounts of propranolol. Studies in vivo and in vitro have indicated that the actions of enoximone are direct and not mediated by stimulation of adrenergic receptors, histaminic receptors, cholinergic receptors, Ca++-adenosine triphosphatase, Mg++-adenosine triphosphatase, adenyl cyclase or inhibition of Na+, K+-adenosine triphosphatase. However, enoximone reversed the depressant effects of verapamil in the dog heart-lung preparation; this suggests that its action resulted in the activation of slow calcium channels. Enoximone was found to be potent and highly selective inhibitor of a high affinity cyclic adenosine monophosphate-phosphodiesterase type IV-phosphodiesterase from dog heart, whereas standard inhibitors (e.g., 3-isobutyl-1-methylxanthine and papaverine) inhibit all 3 cardiac phosphodiesterases. Further, enoximone produced an increase in cyclic adenosine monophosphate, but not cyclic guanosine monophosphate, in the isolated, blood perfused dog papillary muscle during the peak inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidant properties of 2-imidazolones and 2-imidazolthiones.

Uric acid has been postulated to be an important antioxidant and free radical scavenger in humans. Other purines, such as xanthine, that lack an 8-oxo group on the imidazole ring do not show antioxidant properties. For this reason, the antioxidative activities of 2-imidazolones and 2-imidazolthiones were compared to that of uric acid. 2-Imidazolthiones reacted with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) at rates comparable to those of uric acid and other antioxidants. 2-Imidazolones also reacted with DPPH, although at a much slower rate than the 2-imidazolthiones. The 2-imidazolthiones protected oxyhemoglobin from oxidation to methemoglobin by sodium nitrite; the 2-imidazolones had little effect on the oxidation of oxyhemoglobin by nitrate. Most of the 2-imidazolthiones and 2-imidazolones protected both porcine and bovine erythrocytes from hemolysis by t-butyl hydroperoxide. Although 2-imidazolthiones were more reactive than 2-imidazolones in the assays using DPPH and the oxidation of oxyhemoglobin, both types of compounds may be useful as antioxidants in vivo.

4-Aroyl-1,3-dihydro-2H-imidazol-2-ones: a new class of cardiotonic agents. 2. Effect of 4-pyridoyl substituents and related compounds.

A group of 4-pyridoyl-1,3-dihydro-2H-imidazol-2-ones was prepared and tested for inotropic activity in the anesthetized dog. Positive inotropic effects as well as increases in heart rate and decreases in blood pressure were noted for most of these compounds. One of the compounds (8) is currently undergoing clinical trials for the treatment of congestive heart failure.

4-Aroyl-1,3-dihydro-2H-imidazol-2-ones, a new class of cardiotonic agents.

A series of 4-aroyl-1,3-dihydro-2H-imidazol-2-ones was synthesized and evaluated for pharmacological activity in the anesthetized dog. Most members of this series produced dose-related increases in cardiac contractile force as well as relatively minor increases in heart rate and decreases in systemic arterial blood pressure that were not blocked by propranolol. In general, 4-methoxy or 4-methylthiobenzoyl substitution afforded compounds of greatest inotropic potency. 1,3-Dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-one (6) was shown to produce a dose-related positive inotropic effect and reverse the depressant effect of pentobarbital on cardiac pump function in the dog heart-lung preparation. The cardiotonic activity of this series may have important utility in the treatment of congestive heart failure. 1,3-Dihydro-4-[4-(methylthio)benzoyl]-5-methyl-2H-imidazol-2-one (17) was chosen for human studies and is currently undergoing clinical trials.

beta-lactam antibiotics derived from nitrogen heterocyclic acetic acids. 2. Cephalosporin derivatives.

Three cephalosporin derivatives were prepared from 1,4-dihydro-4-oxypyridine-1-acetic acid. These were the 7-aminocephalosporanic acid (7-ACA) derivative and the compounds with 5-methyl-1,3,4-thiadiazol-2-thiol and 1-methyl-1,2,3,4-tetrazole-5-thiol at C-3 of the cephalosporin nucleus. The antibacterial activity of the 7-ACA derivative was comparable to cephalothin, and that of the other two derivatives was comparable to cefazolin. The 7-ACA derivative, compared to cephalothin, was significantly less metabolized, was less protein bound, and had a longer half life.

Orally active cephalosporins and penicillins.

A number of orally active cephalosporins and penicillins with interesting biological activity were synthesized. Two of these, 7-[[[3,4-(methylenedioxy)phenyl]glycyl]amino]deacetoxycephalosporanic acid and 7-[[2-(2,3-dihydro-5-benzofuranyl)glycyl]amino]deacetoxycephalosporanic acid were considerably more active than cephalexin both in vitro and in vivo against staphylococcal and streptococcal infections.