Synthesis and in vitro evaluation of a series of diketopiperazine inhibitors of plasminogen activator inhibitor-1.

We have synthesized and evaluated a series of diketopiperazine-based inhibitors of PAI-1. These studies resulted in the identification of 34 which inhibited PAI-1 in vitro with an IC(50)=0.2 microM. The synthesis and SAR of these compounds are described.

Nutrient requirements versus supply in the dairy cow: strategies to account for variability.

Dairy producers must overcome substantial challenges to achieve milk outputs > 14,000 kg of milk/yr per cow within the next decade. To obtain high productivity, a more complete comprehension of the dynamics of metabolism, nutrient utilization, and nutrient absorption will enable better prediction of the efficiency of utilization of these nutrients. A better understanding of the dynamics of rumen function and a more accurate prediction of nutrient flow from the rumen are necessary. Grouping strategy and group feeding behavior influence cow productivity and farm profitability. Understanding of the variance of individual cow responses to management practice is critical. Feeding system design and management and diet formulation techniques need to be developed that recognize the dynamic nature of cow physiology and the variability in feedstuffs and cow requirements. These concepts need to be integrated into total farm management and require the use of new computer modeling technologies.

Comparison of in vitro techniques to the in situ technique for estimation of ruminal degradation of protein.

The accuracy with which the Streptomyces griseus, ficin, and neutral protease with amylase in vitro methods could be used to predict in situ protein degradation of concentrate feeds was evaluated. Four types of soy products and two types of distillers grains were incubated using each of the four techniques for .5, 1, 2, 4, 8, 12, 24, and 48 h. The percentages of initial CP that remained undegraded over time were determined. Comparison of the degradation curves and contrast analysis of the data indicated that the in vitro methods generated degradability estimates in conflict with those obtained by the in situ method. However, the neutral protease with amylase method ranked the test feeds according to the extent of CP degradation at 24 h most similar to that in situ. Regression equations developed with the neutral protease with amylase degradability estimates explained 78, 76, and 74% of the variation in the in situ estimates obtained after 12, 18, and 24 h of incubation, respectively. At least 69% of the variation in the 18-h in situ estimates could be explained by the neutral protease with amylase estimates obtained after 1, 2, 4, 8, and 12 h of incubation. Little relationship was found between the ficin and S. griseus versus in situ results. Although none of the in vitro methods resulted in degradation curves consistently related to those generated by the in situ technique, relationships were found between protein degradability estimates obtained by the neutral protease with amylase method at specific time points and those obtained by the in situ technique.