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Embryotoxicity studies on irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1,4-dihydro-4-oxo-quinolone-3-carboxylic acid, CAS-91524-15-1), a new fluoroquinolone antibacterial agent, were performed in rats and rabbits. Oral administration of irloxacin during the fetal period of organogenesis to pregnant rats and rabbits at dose levels of up to 1000 and 350 mg/ kg/d, respectively, elicited no evidence of teratogenicity. During the first days of treatment, transient stasis in body weight increase was observed in rat dams receiving doses of 350 or 1000 mg/ kg/d, and reduced food consumption was obeserved in those receiving 1000 mg/kg/ d. Necropsy on day 20 of gestation showed dosage related increase in liver and kidney weights in all rat treated groups. Rabbit dams receiving 350 mg/ kg/d showed during the first days of treatment decrease in body weight, and decreased food consumption and faecal output. Also, four females receiving 350 mg/ kg/d aborted between days 18 and 20 of gestation. Rat fetuses in the 350 and 1000 mg/kg/d showed decreased body weight, and a decrease in placental weights was observed in the 1000 mg/kg/ d group. No retardations or malformations were observed in rat or rabbit fetuses at any tested dose level. For maternal and embryo-fetal effects 100 and 150 mg/kg/d can be considered as the no-effect-level (NOEL) for rats and rabbits, respectively.

The preparation of a series of substituted indoles coupled to six- and seven-membered cyclic lactams is described and their role as human glycogen phosphorylase a inhibitors discussed. The SAR of the indole moiety and lactam ring are presented.

A new class of diacid analogues that binds at the AMP site not only are very potent but have approximately 10-fold selectivity in liver versus muscle glycogen phosphorylase (GP) in the in vitro assay. The synthesis, structure, and in vitro and in vivo biological evaluation of these liver selective glycogen phosphorylase inhibitors are discussed.

Herein we report the preparation of a combinatorial library of compounds with potent CCR5 binding affinity. The library design was aided by SAR generated in a traditional medicinal chemistry effort. Compounds with novel combinations of subunits were discovered that have high binding affinity for the CCR5 receptor. A potent CCR5 antagonist from the library, compound 11 was found to have moderate anti-HIV-1 activity.

Background: Granzyme B, one of the most abundant granzymes in cytotoxic T-lymphocyte (CTL) granules, and members of the caspase (cysteine aspartyl proteinases) family have a unique cleavage specificity for aspartic acid in P1 and play critical roles in the biochemical events that culminate in cell death. Results: We have determined the three-dimensional structure of the complex of the human granzyme B with a potent tetrapeptide aldehyde inhibitor. The Asp-specific S1 subsite of human granzyme B is significantly larger and less charged than the corresponding Asp-specific site in the apoptosis-promoting caspases, and also larger than the corresponding subsite in rat granzyme B. Conclusions: The above differences account for the variation in substrate specificity among granzyme B, other serine proteases and the caspases, and enable the design of specific inhibitors that can probe the physiological functions of these proteins and the disease states with which they are associated.

Di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), based on high-normality linear oxo-alcohols, have been assessed for their impact upon reproductive performance in Sprague-Dawley rats. Rats were continuously exposed to either D79P or D911P at dietary levels of 0%, 0.1%, 0.5%, or 1.0% over two generations. Selected F(0) offspring (F(1) generation) were exposed to the same dietary concentration of D79P or D911P as the respective F(0) animals, and were mated to produce F(1) offspring. Both D79P and D911P markedly reduced body weight gain in F(0) and F(1) adult males at the highest dose, but females were affected to a lesser extent. There was no impairment of fertility, fecundity, or development in either generation, but body weights of offspring in the 1.0% D79P and 1.0% D911P groups were slightly and transiently reduced over the weaning period. Although decreases in the weight of several organs were accounted for by depressed body weight, ovary weights were reduced in both generations exposed to 1.0% D79P, and epididymidal weights were slightly reduced in adults of both generations exposed to 1.0% D911P. However, ovarian function-assessed by the oestrus cycle and mating behaviour-and epididymidal sperm concentration, motility, and morphology were unaffected by either substance. Treatment resulted in liver changes, particularly in males, characterised by increased liver weight in young animals, histopathologic changes and reduced organ weight in mature animals, and an increase in palmitoyl CoA oxidase activity. In conclusion, neither D79P nor D911P impaired reproductive function in rats when administered in the diet at levels that induce systemic toxicity, and the NOAEL for effects on reproduction in the rat is 0.5% for both D79P and D911P.

The need to routinely perform a two-generation study to assess reproductive performance is under debate. This review has analysed the results from 22 consecutive Two-Generation Reproduction Toxicity Studies performed within our laboratories, to determine the value of mating each generation in the detection of treatment-related effects on reproductive performance. The chemicals included 13 agrochemicals, 5 industrial chemicals and 4 food additives. Four chemicals (all from the agrochemical group) were found to have clear treatment-related effects and in three studies effects were confined to the second (F1) generation. For the three studies with second (F1) generation effects, we applied the triggers, proposed by the Agricultural Chemical Safety Assessment (ASCA) Technical Committee of HESI, for extension of the one-generation study and found that mating of the second (F1) generation would have been triggered in these studies by effects on the F1 offspring growth and sexual maturation. No effects were seen in the original parental (F0) generation which would have activated the change from a one- to a two-generation study.

We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.

The synthesis of a series of novel dihdyropyridine diacid glycogen phosphorylase inhibitors is presented. SAR and functional assay data are discussed, along with the effect of a single inhibitor on blood glucose in a diabetic animal model.

A novel class of small molecule human granzyme B inhibitors is reported. Compound 20 has a K(i) of 7 nM against human granzyme B and blocks CTL mediated apoptosis with an IC(50) of 3 micromolar.