Understanding DP receptor antagonism using a CoMSIA approach.

A Comparative Molecular Similarity Indices Analysis (CoMSIA) was performed for 2,6-substituted-4-monosubstituted aminopyrimidine antagonists of prostaglandin D(2) receptor (DP). Both two-component (Q(2) = 0.63, R(2) = 0.82, SEE = 0.47 pIC(50)) and three-component (Q(2) = 0.70, R(2) = 0.91, SEE = 0.36 pIC(50)) CoMSIA models were established. Two hydrogen-bond acceptors with spatial separation of about 8Å are shown as optimal for binding. A large hydrophobic center that separates the two acceptors confers to the potency of the 2,6-substituted-4-monosubstituted aminopyrimidine. The models were used to predict IC(50) values for compounds which had functional groups different from those in the training set.

Low intensity, mixed livestock grazing improves the breeding abundance of a common insectivorous passerine.

Livestock grazing is a major driver of ecosystem change and has been associated with significant declines in various bird species in Britain and worldwide. However, there is little experimental evidence to show how grazing affects bird populations. We manipulated livestock densities in a replicated field experiment and found that mixed sheep and cattle grazing, at low intensity, improved the breeding abundance of a common upland passerine, the meadow pipit Anthus pratensis, after two years. Plots stocked with sheep alone (at high or low density) or not stocked at all held fewer pipit territories. Despite a year-on-year decline in pairs of meadow pipits in intensively grazed plots, we found no effect of sheep number on breeding abundance. Our results support the hypothesis that mixed species of herbivores generate greater heterogeneity in vegetation structure, which modifies prey availability, resulting in a greater abundance of birds. The results of our study should inform the management of grassland areas and enhance the abundance of some bird species, particularly in areas that have seen significant shifts from mixed livestock grazing to grazing dominated by single species of animals.

Optimization of the beta-aminoester class of factor Xa inhibitors. Part 1: P(4) and side-chain modifications for improved in vitro potency.

A systematic modification of the C(3) side-chain of the beta-aminoester class of factor Xa inhibitors and a survey of P(4) variations is described. These changes have resulted in the identification of sub-nanomolar inhibitors with improved selectivity versus related proteases. Coagulation parameters (i.e., APTT doubling concentrations) are also improved.

Optimization of the beta-aminoester class of factor Xa inhibitors. Part 2: Identification of FXV673 as a potent and selective inhibitor with excellent In vivo anticoagulant activity.

Further optimization of the beta-aminoester class of factor Xa (fXa) inhibitors is described culminating in the identification of 9c (FXV673), a potent and selective factor Xa inhibitor with excellent in vivo anticoagulant activity. An X-ray structure of FXV673 bound to human fXa is also presented. Based on its selectivity, potent in vivo activity and favorable pre-clinical safety profile, FXV673 was selected for further development and is currently undergoing clinical trials.