Discovery of potent CCR4 antagonists: Synthesis and structure–activity relationship study of 2,4-diaminoquinazolines

A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure–activity relationships and led the identification of 2-(1,4′-bipiperidine-1′-yl)-N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine 14a, which showed potent inhibition in the [35S]GTPγS-binding assay (IC50 = 18 nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC50 = 140 nM, 39 nM).

A new series of potent competitive CCR4 antagonists were discovered. Compound 14a showed potent inhibition in the [35S]GTPγS-binding assay, and blocked the chemotaxis of human and mouse CCR4-expressing cells.Figure optionsDownload as PowerPoint slide