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Polysubstituted Pyrimidines as Potent Inhibitors of Prostaglandin E 2 Production: Increasing Aqueous Solubility
Author(s) -
Kalčic Filip,
Kolman Viktor,
Zídek Zdeněk,
Janeba Zlatko
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100263
Subject(s) - solubility , chemistry , moiety , substituent , pyrimidine , amine gas treating , aqueous solution , prostaglandin , derivative (finance) , stereochemistry , medicinal chemistry , organic chemistry , biochemistry , financial economics , economics
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 E 2 (PGE 2 ) 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 PGE 2 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 PGE 2 production) compared with the parent compound (15 % of remaining PGE 2 production).