Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors

The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. The series was found to have much improved CDK2 inhibition and potent in vitro anti-proliferative effects against cancer cell lines. Control of overall lipophilicity was important to achieve good in vitro potency along with acceptable physiochemical properties and margins against inhibition of both CYP isoforms and the hERG potassium ion channel. A compound with an attractive overall balance of properties was profiled in vivo and possessed suitable physiochemical and pharmacokinetic profiles for oral dosing.     

The effect of exercise training modality on serum brain derived neurotrophic factor levels in individuals with type 2 diabetes

Introduction

Brain derived neurotrophic factor (BDNF) has been implicated in memory, learning, and neurodegenerative diseases. However, the relationship of BDNF with cardiometabolic risk factors is unclear, and the effect of exercise training on BDNF has not been previously explored in individuals with type 2 diabetes.

Methods

Men and women (N = 150) with type 2 diabetes were randomized to an aerobic exercise (aerobic), resistance exercise (resistance), or a combination of both (combination) for 9 months. Serum BDNF levels were evaluated at baseline and follow-up from archived blood samples.

Results

Baseline serum BDNF was not associated with fitness, body composition, anthropometry, glucose control, or strength measures (all, p>0.05). Similarly, no significant change in serum BDNF levels was observed following exercise training in the aerobic (−1649.4 pg/ml, CI: −4768.9 to 1470.2), resistance (−2351.2 pg/ml, CI:−5290.7 to 588.3), or combination groups (−827.4 pg/ml, CI: −3533.3 to1878.5) compared to the control group (−2320.0 pg/ml, CI: −5750.8 to 1110.8). However, reductions in waist circumference were directly associated with changes in serum BDNF following training (r = 0.25, p = 0.005).

Conclusions

Serum BDNF was not associated with fitness, body composition, anthropometry, glucose control, or strength measures at baseline. Likewise, serum BDNF measures were not altered by 9 months of aerobic, resistance, or combination training. However, reductions in waist circumference were associated with decreased serum BDNF levels. Future studies should investigate the relevance of BDNF with measures of cognitive function specifically in individuals with type-2 diabetes.     

Selecting a more realistic uncertainty factor: Reducing compounding effects of multiple uncertainties

Available toxicology datasets provide a unique opportunity to validate some of the currently used Uncertainty Factors in the development of acceptable exposure levels for noncancer effects. Toxicity studies from two separate sources, the FAO/WHO database on pesticides (1978–1987) and the Monsanto database (through 1988) were chosen to evaluate three of the five currently used Uncertainty Factors. Interspecies differences in NOELs between the three mammalian species evaluated are equal to or less than a factor of 10 for both the FAO/WHO data and the Monsanto data in greater than 90% of the cases evaluated. Median values for the comparison of interspecies NOELs were 3.0 or less for all comparisons except the comparison between the mouse and rat for the Monsanto dataset where the median value was 7.5. Analyses of the Monsanto toxicity database show that the reprotoxicity NOELs were always equivalent to or higher than the chronic or subchronic NOELs for the same material. Therefore, even without conduct of a specific study to address reproductive effects, reasonable protection from adverse reproductive effects can be afforded by use of either subchronic or chronic study NOELs without application of UFD. The median ratio of subchronic NOELs and chronic NOELs was 4, and for a majority of the studies the difference between the NOELs was within one order of magnitude. Our analysis aids in validating the assumption that the upperbound for individual uncertainties maybe accounted for by use of 10‐fold uncertainty factors. However, the current U.S. Environmental Protection Agency (USEPA) reference doses/concentrations may be overly conservative because upperbounds of each of the uncertainty factors are used and each of the uncertainty factors are considered to be independent variables. Because uncertainties are probably not independent variables, the influence of compounding upperbounds when multiple uncertainty factors are used is generally only considered when four or more areas of uncertainty are outstanding. When multiple uncertainties exist, we recommend upperbound estimates only be used for the first two Uncertainty Factors, and median values be used to account for the remaining uncertainties.     

Cell-wall structure,mitosis and urease activity in Torulopsis species of high GC content

Five Torulopsis species, in which, characteristically, the mean molar percentage of guanine plus cytosine of the DNA bases (GC content) is above 50%, were examined to determine their cell-wall structure; the mode of bud formation; course of mitosis and their urease activity. The two urease-negative species, T. gropengiesseri (% GC 57.1) and T. silvatica (% GC 56.3), were found to possess affinitive properties which characterize perfect ascomycetous yeast species. In the urease-positive species, T. fujisanensis (% GC 65.0–66.1), T. ingeniosa (% GC 55.6) and T. philyla (% GC 63.9), there appeared to be a correlation between pronounced urease activity and the affinitive properties which characterize perfect basidiomycetous yeast species. Pronounced urease activity has, however, also been found in the ascomycetous species Schizosaccharomyces pombe. Consequently neither high GC ratios nor the presence of urease activity when considered individually, can be taken as reliable criteria when attempting to establish the affinity of yeasts the perfect states of which are not known, with the Basidiomycetes. A strain of the ascomycetous species Sclerotinia trifoliorum was examined by electron microscopy for comparative purposes.     

Repeated batch cultivation of rBHK cells on Cytodex 3 microcarriers: antithrombin III,amino acid,and fatty acid metabolic quotients

Anchorage-dependent human antithrombin III-producing recombinant baby hamster kidney (rBHK) cells were cultivated on Cytodex 3 microcarriers in repeated batch mode. During a 3-month experiment four different low-serum (0.025% fetal bovine serum) or serum-free medium formulations were evaluated for (a) the initial growth phase of cells and (b) the subsequent production phase, whereby two free fatty acid (FFA) supplements were examined with respect to their growth-promoting and product-formation-enhancing properties. Selected nutrient and (by)product consumption and production rates (including those for antithrombin III, amino acids, and fatty acids) are reported. The calculated metabolic quotients reflect the prevailing slow growth conditions ( approx. 0.06 day^–1) associated with microcarrier cultures. Specific antithrombin III productivities vary singificantly as a function of the feed medium supplementation with FFA. Correspondence to: G. Schmid