Polysubstituted Pyrimidines as Potent Inhibitors of Prostaglandin E₂ Production: Increasing Aqueous Solubility

Water solubility is one of the key features of potential therapeutic agents. In order to enhance the low water solubility of the parent 5-butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine, a potent inhibitor of prostaglandin E₂ (PGE₂ ) production, we synthesized and evaluated a new series of derivatives in which the butyl group at the C5 position of the pyrimidine ring was replaced with a less lipophilic substituent, preferably with a hydrophilic aliphatic moiety. Except for the 5-cyanopyrimidine derivative, all target compounds exhibited increased (2.7-87-fold) water solubility relative to the parent compound. Although nontoxic in mouse peritoneal cells, the prepared compounds were either equipotent or weaker inhibitors of PGE₂ production than the parent compound. The most promising compound from the series was found to be the 5-(2,5,8,11-tetraoxadodecyl)pyrimidine derivative (with three polyethylene glycol units at the C5 position), which exhibited 32-fold higher water solubility and only slightly weaker inhibitory activity (22 % of remaining PGE₂ production) compared with the parent compound (15 % of remaining PGE₂ production).