Spirodiketopiperazine-based CCR5 antagonists: Lead optimization from biologically active metabolite

Key modification introducing a hydroxyl group on side chain to improve CCR5 antagonistic activity as well as in vitro anti-HIV activity by the application of the metabolite’s information of 1. Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from β-substituted (2 R,3 R)-2-amino-3-hydroxypropionic acid showed improved inhibitory activities against the binding of MIP-1α to human CCR5, compared with the non-hydroxylated derivatives and the other isomers.