ABSTRACT
The structure-activity relationship among a series of novel pyrazolidinone antibacterial agents is described. Specifically, the effect of modification of the side chain attached to the nitrogen at C-7 was explored in an attempt to improve the potency and spectrum of activity. This approach was successful in identifying several compounds having good in vitro profiles. These top candidates were then evaluated for their activity in vivo, and their pharmacokinetic behavior in various animal models was explored. This information proved critical for the identification of candidates for clinical evaluation.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic , Bridged Bicyclo Compounds/pharmacology , Bridged Bicyclo Compounds/pharmacokinetics , Pyrazoles/pharmacology , Pyrazoles/pharmacokinetics , Thiazoles/pharmacology , Thiazoles/pharmacokinetics , Animals , Anti-Bacterial Agents/chemistry , Bridged Bicyclo Compounds/chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Half-Life , Macaca mulatta , Male , Mice , Mice, Inbred Strains , Microbial Sensitivity Tests , Pyrazoles/chemistry , Rats , Rats, Sprague-Dawley , Staphylococcus/drug effects , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
Gemcitabine was given intravenously to female mice on gestation days (GD) 6-15 at doses of 0, 0.05, 0.25, or 1.5 mg/kg/day (0, 0.15, 0.75, or 4.5 mg/m2/day, respectively). Animals assigned to the teratology segment (25/group) were killed on GD 18 for examination of maternal hematologic parameters and organ weights, as well as fetal viability, weights, and morphology. The postnatal segment females (20/group) were allowed to deliver, and offspring physical, behavioral, and reproductive parameters were monitored. After offspring weaning, these dams were killed for hematologic and organ weight evaluations. At necropsy, 3 days after the final dose, the teratology segment dams showed dose-related increases in spleen and thymus weights. These changes were accompanied by a dose-related decrease in leukocytes and modest increases in mean corpuscular volume (MCV) and hemoglobin (MCH) at the two higher doses. On postpartum day (PPD) 21, the dams in the postnatal segment showed no treatment-related effects on these organ weights or hematologic parameters, indicating recovery of these maternal parameters within 3.5 weeks following termination of treatment. The decreases in maternal body weight and food consumption observed during gestation, and in liver and uterine weights at term in the 1.5 mg/kg/day group, were considered to be secondary to a high rate of prenatal mortality, evidenced by increased resorptions in the teratology segment and decreased live litter size in both segments of the study. Additional indications of developmental toxicity in this dose group were an increased incidence of malformations, primarily cleft palate, decreased fetal weights in the teratology segment, and decreased neonatal survival in the postnatal segment.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Abnormalities, Drug-Induced/etiology , Antimetabolites, Antineoplastic/toxicity , Deoxycytidine/analogs & derivatives , Fetal Resorption/chemically induced , Pregnancy, Animal/drug effects , Abnormalities, Drug-Induced/embryology , Animals , Behavior, Animal/drug effects , Body Weight/drug effects , Deoxycytidine/toxicity , Dose-Response Relationship, Drug , Eating/drug effects , Erythropoiesis/drug effects , Female , Gestational Age , Hematopoiesis/drug effects , Male , Mice , Mice, Inbred Strains , Organ Size/drug effects , Pregnancy , Reproduction/drug effects , Spleen/drug effects , Spleen/pathology , Thymus Gland/drug effects , Thymus Gland/pathology , GemcitabineABSTRACT
The synthesis and biological evaluation of novel 1-carba-1-dethiacephalosporins exhibiting activity against anaerobic pathogens are described. The nitrothiazole substituent was determined to be crucial to maintaining this activity. The pharmacokinetic parameters and initial toxicological profile of the lead compound are discussed.
Subject(s)
Bacteria, Anaerobic/drug effects , Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Animals , Cephalosporins/pharmacokinetics , Male , Rats , Rats, Sprague-DawleyABSTRACT
The preparation and biological evaluation of a series of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoximinoacetamido]cep halosporins, substituted at the 3'-position with monocyclic or bicyclic nitrogen-containing heterocycles are described. The resulting family of parenteral compounds displays a broad spectrum of antibacterial activity. Some compounds exhibit a similar level of Gram-negative activity to that of the "third-generation" cephalosporins with increased staphylococcal activity. The in vitro and in vivo antimicrobial activity, structure-activity relationships, beta-lactamase stability, and in vitro and in vivo pharmacological evaluations are presented.
Subject(s)
Cephalosporins/pharmacology , Animals , Blood Pressure/drug effects , Cephalosporins/metabolism , Cephalosporins/pharmacokinetics , Chemical Phenomena , Chemistry , Dogs , Enterobacter/drug effects , Escherichia coli/drug effects , Female , Guinea Pigs , Half-Life , Heart Rate/drug effects , Klebsiella pneumoniae/drug effects , Macaca mulatta , Male , Mice , Molecular Structure , Parasympatholytics/pharmacology , Pseudomonas aeruginosa/drug effects , Rats , Serratia marcescens/drug effects , Staphylococcus aureus/drug effects , Streptococcus/drug effects , Structure-Activity Relationship , beta-Lactamases/metabolismABSTRACT
A series of structurally unique 1-carba-1-dethiacephems is described. The structural stability of the 1-carba-1-dethiacephem nucleus was essential for the preparation of this series of 3-quaternary ammonium carbacephems. The known p-nitrobenzyl 7 beta-(phenoxyacetamido)- 3-[(trifluoromethyl)sulfonyl]oxy]-1-carba-1-dethia-3-cephem- 4-carboxylate served as both a quaternization substrate as well as a precursor to derivatives such as allyl 7 beta-[[2-[allyloxy)carbonyl]amino-4- thiazoly] (methoxyimino)acetyl]amino]-3-[(trifluoromethyl) sulfonyl] oxy]-1-carba-1-dethia-3-cephem-4-carboxylate. Quaternization of these enol triflates was accomplished either by dissolution in acetonitrile containing the base or by dissolution in the base, with or without warning to 50 degrees C. Bases nucleophilic enough to displace the triflate include a variety of substituted pyridines and N-methylimidazole. Deprotection then produced a very active series of 1-[7 beta-[(2-amino- 4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo- 1-azabicyclo[4.2.0]oct-2-en-3-yl] quaternary ammonium hydroxide inner salts. These compounds were extremely potent antibacterials against a broad range of Gram-positive and -negative bacteria including constitutive cephalosporinase producers, such as Enterobacter cloacae. The compounds exhibit similar hydrolysis kinetics and pharmacokinetics to the analogous cephalosporin-3'-quaternary ammonium salts.
Subject(s)
Cephalosporins/pharmacology , Animals , Cephalosporins/chemical synthesis , Cephalosporins/pharmacokinetics , Chemical Phenomena , Chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Models, Molecular , Rats , Structure-Activity RelationshipABSTRACT
A number of 7-(arylacetamido)-3-substituted cephalosporins were prepared and tested in animals for oral absorbability. Bioavailability in mice, rats, dogs, and monkeys was determined after oral or parenteral administration. Oral bioavailability of five compounds selected for more intensive study was generally higher than that of penicillin V in all species tested. The results of ED50 testing against experimental infections in mice generally supported the bioavailability studies. Antibiotic activities were evaluated against Gram-positive and Gram-negative organisms with some derivatives expressing in vitro activity similar to cefaclor. The plasma half-life in rats was relatively short and the plasma curves were strongly influenced by probenecid, indicating rapid renal secretion. Some 7-(arylacetamido)-3-chloro cephalosporins are orally absorbed in animals to a greater extent than penicillin V, and antibacterial agent of proven clinical utility.
