1233707-23-7Relevant articles and documents
1-(5-carboxyindol-1-yl)propan-2-one inhibitors of human cytosolic phospholipase A2α with reduced lipophilicity: Synthesis, biological activity, metabolic stability, solubility, bioavailability, and topical in vivo activity
Drews, Andreas,Bovens, Stefanie,Roebrock, Kirsten,Sunderk?tter, Cord,Reinhardt, Dirk,Sch?fers, Michael,Van Der Velde, Andrea,Schulze Elfringhoff, Alwine,Fabian, J?rg,Lehr, Matthias
experimental part, p. 5165 - 5178 (2010/09/18)
Indole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 were previously reported to be potent inhibitors of human cytosolic phospholipase A2α (cPLA2α). In continuation of our attempts to develop clinical active cPLA2α inhibitors, a series of structurally related indole-5-carboxylic acids with reduced lipophilicity was synthesized and tested for cPLA2α-inhibitory potency. Furthermore, the thermodynamic solubility of these compounds and their metabolic stability in rat liver microsomes were evaluated. With an IC 50 of 0.012 μM against the isolated enzyme, compound 36 was one of the most potent cPLA2α inhibitors that emerged during the structure-activity relationship study. Concomitantly, 36 possessed the highest water solubility (212 μg/mL at pH 7.4) of all new target compounds. Despite these favorable properties, peroral application of 36 (100 mg/kg) in mice only led to low concentrations of the substance in blood plasma. A very high plasma clearance was observed after intravenous administration of 36 (10 mg/kg). However, in a topical murine model of contact dermatitis, 36 showed a pronounced anti-inflammatory in vivo activity.
