Optimization of 2,4-diaminopyrimidines as GHS-R antagonists: Side chain exploration

The synthesis and structure–activity relationships of the 4- and 6-substituents of 2,4-diaminopyrimidine-based growth hormone secretagogue receptor (GHS-R) antagonists are described. Diaminopyrimidines with 6-norbornenyl (4n) and 6-tetrahydrofuranyl (4p) substitutents were found to exhibit potent GHS-R antagonism and good selectivity (∼1000-fold) against dihydrofolate reductase.

The synthesis and structure–activity relationships of the 4- and 6-substituents of 2,4-diaminopyrimidine-based growth hormone secretagogue receptor (GHS-R) antagonists are described. Diaminopyrimidines with 6-norbornenyl (4n) and 6-tetrahydrofuranyl (4p) substitutents exhibited potent GHS-R antagonism and good selectivity (∼1000-fold) against dihydrofolate reductase.Figure optionsDownload as PowerPoint slide