ABSTRACT
Novel fusidic acid type antibiotics having flexible side chains are described. Saturation of the double bond between C-17 and C-20 of fusidic acid produces four stereoisomers differing in the configuration at C-17 and C-20. The structure-activity relationship of the stereoisomers was studied using computer-assisted analyses of low-energy conformations and crystallographic data. Only one of the four stereoisomers showed potent antibiotic activity comparable with that of fusidic acid, whereas the other three stereoisomers retained little or no activity. The orientation of the side chain is crucial, and there is only a limited space for bioactive side chain conformations. This investigation demonstrates the essential role of the side chain conformations in relation to antibacterial activity and contradicts earlier assumptions that the Delta17(20) bond is an essential feature in the molecule.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Fusidic Acid/analogs & derivatives , Fusidic Acid/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Colony Count, Microbial , Fusidic Acid/chemistry , Fusidic Acid/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular ConformationABSTRACT
1. The absorption, distribution, metabolism and excretion of 2-[3'-(2"-quinolyl-methoxy)phenylamino]benzoic acid (QMPB), a novel leukotriene D4/E4 antagonist, were investigated in rat, dog, guinea pig and man. 2. The oral absorption of the potassium salt of QMPB was rapid and almost complete (90%) in rats, and about 50% in dogs. In man, high oral bioavailability was indicated. Absorption in dogs of the zwitterion form was only 7%. 3. The distribution of 3H-QMPB was examined in rats and guinea pigs. Whole-body autoradiography in rats showed that radioactivity was concentrated predominantly in the liver, bile and intestinal lumen, after both oral and i.v. administration. 4. A major metabolite was identified as the O-ester beta-glucuronide of QMPB. 5. Renal excretion in rat, dog and man was very low. In rat, almost complete biliary excretion of QMPB as the glucuronide conjugate was demonstrated. 6. Pronounced enterohepatic circulation of QMPB was demonstrated in rats, and the plasma concentration curves and the negligible renal excretion in dog and man also indicate enterohepatic circulation in these species.
Subject(s)
Quinolines/pharmacokinetics , SRS-A/analogs & derivatives , SRS-A/antagonists & inhibitors , Adult , Animals , Biological Availability , Dogs , Female , Guinea Pigs , Humans , Leukotriene E4 , Male , Middle Aged , Quinolines/metabolism , Rats , Rats, Inbred Strains , Species Specificity , Tissue Distribution , Xenobiotics/metabolism , Xenobiotics/pharmacokineticsABSTRACT
1. The antihypertensive agent pinacidil is eliminated from the body mainly by biotransformation in the liver, followed principally by renal excretion of the metabolites. 2. The metabolism and elimination of pinacidil is similar in rat, dog and man, and is independent of the route of administration. 3. After an oral dose, the 24 h urinary excretion of unchanged pinacidil is 13, 4, and 5% in rat, dog and man, respectively. Faecal excretion in the rat and dog is 2 and 4%. 4. In rat, dog and man the main biotransformation product is the pyridine-N-oxide of pinacidil. Following oral administration of pinacidil, 40, 54 and 54%, respectively, is excreted in the urine as the N-oxide during the first 24 h, and less than 1% in the faeces in rat and dog. 5. Three unidentified minor metabolites were found in plasma, urine and faeces in rat and dog. 6. The major metabolite, the pyridine-N-oxide of pinacidil, has an anti-hypertensive potency about a quarter of that of pinacidil. In animals and human volunteers with normal kidney function, however, the plasma concn. of the N-oxide are always lower than those of the parent compound, so that the metabolite contributes little to the antihypertensive effect of pinacidil.
Subject(s)
Antihypertensive Agents/metabolism , Guanidines/metabolism , Pyridines/metabolism , Adult , Animals , Biotransformation , Carbon Radioisotopes , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Dogs , Feces/analysis , Female , Humans , Kinetics , Male , Pinacidil , RatsABSTRACT
The hydrolysis of mecillinam in aqueous solution (37 degrees) was studied at pH 2-10. The degradation products observed by TLC and NMR were identified and quantified. Several of these compounds were synthesized. Mecillinam and the key degradation product, (6R)-6-formamidopenicillanic acid, underwent reversible 6-epimerization in basic solution. Some of the thiazolidine derivatives formed epimerized at position 2. In contrast to penicillins, the degradation pattern of mecillinam becomes more complex with increasing pH. Rate constants for some processes are given.
