Synthesis and pharmacokinetic properties of novel cPLA2α inhibitors with 1-(carboxyalkylpyrrolyl)-3-aryloxypropan-2-one structure

1-Benzylindoles as inhibitors of cytosolic phospholipase A2α: synthesis, biological activity, aqueous solubility, and cell permeability

“…The Caco-2 cell permeability was determined as previously described. 22,23 In brief, the test substances were added onto the apical side of the cell layer at a concentration of 10 μM and after 2 h incubation at 37 °C, their concentration and, in the case of 122 also that of its metabolite 186 in the media of the apical and basolateral compartment, was measured by HPLC and MS detection. To determine the substance concentration and the recovery, solutions of the substances were prepared in PBS buffer and measured.…”

“…The substance was added to the apical side of the cell layer at a concentration of 10 μM and its content in the apical and basolateral compartments was determined after 2 h by HPLC and MS detection. 22,23 Preliminary experiments showed that 122 was metabolised in the cells to a more polar metabolite. Based on the mass/ charge ratio, it was assumed to be a metabolite formed by degradation of the pentanoic acid chain around two carbon atoms, probably by β-oxidation in the mitochondria of the cells.…”

“…11 However, these substances were also unsuitable for peroral use, as they are potent substrates of efflux transporters of intestinal cells and are also very quickly reduced in the body by carbonyl reductases to inactive alcohol derivatives. 11,12 To identify new lead structures for cPLA 2 α inhibitors, recently, we have performed a virtual screening 13 inspired by the work of Naylor et al and Gianella-Borradori et al 14,15 Energetically favourable conformers were calculated from a set of structurally related cPLA 2 α inhibitors of Wyeth (now Pfizer) with high potency, 7,10 such as WAY-196025 (2). Of the compounds that were the closest match, several were purchased and tested.…”