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

0543665 - ÚOCHB 2022 RIV DE eng J - Journal Article
Kalčic, Filip - Kolman, Viktor - Zídek, Zdeněk - Janeba, Zlatko
Polysubstituted Pyrimidines as Potent Inhibitors of Prostaglandin E2 Production: Increasing Aqueous Solubility.
ChemMedChem. Roč. 16, č. 18 (2021), s. 2802-2806. ISSN 1860-7179. E-ISSN 1860-7187
R&D Projects: GA TA ČR(CZ) TE01020028
Institutional support: RVO:61388963 ; RVO:68378041
Keywords : anti-inflammatory * prostaglandin E2 * pyrimidines * solubility * synthesis
OECD category: Organic chemistry; Medicinal chemistry (UEM-P)
Impact factor: 3.540, year: 2021
Method of publishing: Limited access
https://doi.org/10.1002/cmdc.202100263

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).
Permanent Link: http://hdl.handle.net/11104/0320847