New phenolic cinnamic acid derivatives as selective COX-2 inhibitors. Design, synthesis, biological activity and structure-activity relationships.

Selective inhibition of cyclooxygenase (COX)-2 enzyme is an important achievement when looking for potent anti-inflammatory agents, with fewer gastrointestinal side effects. In this work, a new series of cinnamic acid derivatives, namely hexylamides, have been designed, synthesized and evaluated in human blood for their inhibitory activity of COX-1 and COX-2 enzymes. From this, new structure-activity relationships were built, showing that phenolic hydroxyl groups are essential for both COX-1 and COX-2 inhibition. Furthermore, the presence of bulky hydrophobic di-tert-butyl groups in the phenyl ring strongly contributes for selective COX-2 inhibition. In addition, a correlation with the theoretical log P has been carried out, showing that lipophilicity is particularly important for COX-2 inhibition. Further, a plasma protein binding (PPB) prediction has been performed revealing that PPB seems to have no influence in the activity of the studied compounds. From the whole study, effective selective inhibitors of COX-2 were found, namely compound 9 (IC50 = 3.0 ±â€¯0.3 µM), 10 (IC50 = 2.4 ±â€¯0.6 µM) and 23 (IC50 = 1.09 ±â€¯0.09 µM). Those can be considered starting point hit compounds for further optimization as potential non-steroidal anti-inflammatory drugs.

Shear-thinning effects of hemodynamics in patient-specific cerebral aneurysms.

Two different generalized Newtonian mathematical models for blood flow, derived for the same experimental data, are compared, together with the Newtonian model, in three different anatomically realistic geometries of saccular cerebral aneurysms obtained from rotational CTA. The geometries differ in size of the aneurysm and the existence or not of side branches within the aneurysm. Results show that the differences between the two generalized Newtonian mathematical models are smaller than the differences between these and the Newtonian solution, in both steady and unsteady simulations.

Sensitivity of hemodynamics in a patient specific cerebral aneurysm to vascular geometry and blood rheology.

Newtonian and generalized Newtonian mathematical models for blood flow are compared in two different reconstructions of an anatomically realistic geometry of a saccular aneurysm, obtained from rotational CTA and differing to within image resolution. The sensitivity of the flow field is sought with respect to geometry reconstruction procedure and mathematical model choice in numerical simulations. Taking as example a patient specific intracranial aneurysm located on an outer bend under steady state simulations, it is found that the sensitivity to geometry variability is greater, but comparable, to the one of the rheological model. These sensitivities are not quantifiable a priori. The flow field exhibits a wide range of shear stresses and slow recirculation regions that emphasize the need for careful choice of constitutive models for the blood. On the other hand, the complex geometrical shape of the vessels is found to be sensitive to small scale perturbations within medical imaging resolution. The sensitivity to mathematical modeling and geometry definition are important when performing numerical simulations from in vivo data, and should be taken into account when discussing patient specific studies since differences in wall shear stress range from 3% to 18%.