A novel rapid throughput phototolerance screen in mice.

A relatively simple, rapid throughput phototolerance screen in small animals would be very useful in early drug development. It could prioritize or select potential lead compounds from among a number of analogs with similar biological activities. This study describes an in vivo mouse phototolerance screen established for that purpose. It also reports phototolerance data with standard reference drugs obtained using this screen.

Structure-activity relationships of quinolone agents against mycobacteria: effect of structural modifications at the 8 position.

A series of quinolones with substitutions at the 8 position has been prepared as part of a study to examine the relationship between structural modifications at this position and activity against mycobacteria. The compounds were prepared by procedures described in the literature and were evaluated for their activities against Mycobacterium fortuitum and Mycobacterium smegmatis. The activities of the compounds against these two organisms were used as a measure of Mycobacterium tuberculosis activity. The results demonstrate that the contribution of the 8 position to antimycobacterial activity was dependent on the substituent at N-1 and was in the order (i) COMe approximately CBr > CCI > CH approximately CF approximately COEt > N > CCF3 when N-1 was cyclopropyl; (ii) N approximately CH > CF > COMe when N-1 was 2,4-difluorophenyl; (iii) N > or = CH when N-1 was tert-butyl; and (iv) N > CH when N-1 was ethyl. In general, derivatives with piperazine substitutions at C-7 were slightly less active against mycobacteria than the analogs with pyrrolidine substitutions, regardless of the pattern of substitution at the 8 position. Several of the best compounds were evaluated for their potential side effects as well as their activities against Mycobacterium aurum, Mycobacterium avium-M. intracellulare, and M. tuberculosis. These agents exhibited biological profiles similar to or better than those of the positive controls ciprofloxacin and sparfloxacin.

In vivo therapeutic efficacies of PD 138312 and PD 140248, two novel fluoronaphthyridines with outstanding gram-positive potency.

PD 138312 and PD 140248 are novel broad-spectrum 7-pyrrolidinyl fluoronaphthyridines with a cyclopropyl or a difluorophenyl substitution at the 1 positions, respectively. They have been demonstrated to have excellent in vitro activity against gram-positive organisms. These compounds were evaluated for their in vivo potencies against acute systemic infections in mice and in a mouse pneumococcal pneumonia model. They were very effective by both the oral and subcutaneous routes of administration. Most remarkable were their comparative median protective values against methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. In general, these compounds were 28- to 100-fold more active than ciprofloxacin against these clinically significant organisms when the drugs were given orally and 10- to 38-fold more active when the drugs were given parenterally. Average ratios of drug concentrations in mice after drug administration by the oral route to that after administration by the subcutaneous route indicate 34 to 44% greater bioavailabilities of PD 138312 and PD 140248 compared with that of ciprofloxacin. In a multidose pneumococcal mouse pneumonia model these new quinolones were extremely effective, with median curative doses of 2 to 2.8 mg/kg of body weight per dose. Ciprofloxacin was ineffective (median curative dose, >100 mg/kg per dose) in this model. Comparative pharmacokinetic studies in mice revealed a relative superiority of PD 140248. Peak levels of PD 140248 in blood after the administration of a single oral 50-mg/kg dose were twice those of PD 138312 and ciprofloxacin, with PD 140248 having a substantially longer half-life. These results indicate that PD 138312 and PD 140248 have excellent therapeutic potential against clinically important gram-positive pathogens when the drugs are administered both orally and parenterally.

In vitro evaluation of cefdinir (FK482), a new oral cephalosporin with enhanced antistaphylococcal activity and beta-lactamase stability.

Cefdinir (FK482), a new oral cephalosporin with enhanced beta-lactamase stability, was tested by microbroth dilution against respiratory, urogenital, and skin and skin-structure bacterial pathogens. Included were beta-lactamase (beta LAC)-producing and -nonproducing isolates. Activity was compared with that of other orally administered beta-lactams. Cefdinir minimum inhibitory concentrations for 90% of isolates MIC90s (microgram/ml) were < or = 0.5 versus beta LAC+/oxacillin-susceptible Staphylococcus, aureus, S. epidermidis, and S. saprophyticus; < or = 0.06 versus Streptococcus groups A and B, and Neisseria gonorrhoeae beta LAC+; 0.125 versus S. pneumoniae penicillin-susceptible and Proteus mirabilis beta LAC+; 0.25 versus beta LAC+ versus strains of Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and K. oxytoca; 0.5 versus Haemophilus influenzae beta LAC-; 1 versus H. influenzae beta LAC+; 4 versus Legionella pneumophila beta LAC+; and 8 versus Enterococcus faecalis beta LAC-strains. Cefdinir was equally effective against both standard and high inocula of S. aureus strains producing A, B, C, or D beta LAC types. MICs were also generated versus quality-control reference strains.

New 8-(trifluoromethyl)-substituted quinolones. The benefits of the 8-fluoro group with reduced phototoxic risk.

A series of 8-(trifluoromethyl)-substituted quinolones has been prepared and evaluated for in vitro and in vivo antibacterial activity, and phototolerance in a mouse phototolerance assay. These analogues were compared to the corresponding series of 6,8-difluoro- and 6-fluoro-8H-quinolones (ciprofloxacin type). Although their in vitro antibacterial activities are less than the 6,8-difluoro analogues, the 8-(trifluoromethyl)quinolones are generally equivalent to their 8H analogues. In vivo, they are comparable to the 6,8-difluoro series and show up to 10-fold improvement in efficacy when compared to their ciprofloxacin counterparts vs Streptococcus pyogenes and Streptococcus pneumonia. In the phototolerance model, the 8-(trifluoromethyl)quinolones are comparable to the 8H-quinolones. Both of these series display much higher no effect doses (greater tolerance) than the corresponding 6,8-difluoroquinolones.