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

ChemMedChem. 2021 May 31. doi: 10.1002/cmdc.202100263. Online ahead of print.ABSTRACTWater-solubility is one of the key features of potential therapeutic agents. In order to enhance poor water-solubility of parent 5-butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine, a potent inhibitor of prostaglandin E 2 (PGE 2 ) production, we synthesized and evaluated a new series of derivatives where the butyl group in the C5 position of pyrimidine ring was replaced with 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 compared to the parent compound. Although non-toxic in mouse peritoneal cells, the prepared compounds were either equipotent or weaker inhibitors of PGE 2 production than the parent compound. The most promising compound from the series was 5-(2,5,8,11-tetraoxadodecyl)pyrimidine derivative (with three polyethylene glycol units in the C5 position), which exhibited 32-fold higher water-solubility and only slightly weaker inhibitory activity (22% of remaining PGE 2 production) compared to the parent compound (15% of remaining PGE 2 production).PMID:34056858 | DOI:10.1002/cmdc.202100263
Source: ChemMedChem - Category: Chemistry Authors: Source Type: research