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

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Abstract

Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from β-substituted (2R,3R)-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.

Graphical abstract

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.

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    Citation Excerpt :

    TAK-779 (dimethyl-(tetrahydro-pyran-4-yl)-{4-[(3-p-tolyl-8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-ammonium chloride; Mr = 531.14) (Shiraishi et al., 2000). Aplaviroc (4-{4-[1-butyl-3-(cyclohexyl-hydroxy-methyl)-2,5-dioxo-1,4,9-triaza-spiro[5.5]undec-9-ylmethyl]-phenoxy}-benzoic acid; Mr = 577.73) (Habashita et al., 2006; Nishizawa et al., 2007, 2010a, 2010b). Vicriviroc ((4,6-dimethyl-pyrimidin-5-yl)-(4-{(S)-4-[(R)-2-methoxy-1-(4-trifluoromethyl-phenyl)-ethyl]-3-methyl-piperazin-1-yl}-4-methyl-piperidin-1-yl)-methanone; Mr = 533.64) (Marozsan et al., 2005).

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