title: Spirodiketopiperazine-based CCR5 antagonists: Lead optimization from biologically active metabolite.
abstract: Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from beta-substituted (2R,3R)-2-amino-3-hydroxypropionic acid showed improved inhibitory activities against the binding of MIP-1alpha to human CCR5, compared with the non-hydroxylated derivatives and the other isomers.
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, Osaka 618-8585, Japan. r.nishizawa@ono.co.jp
authors.forename: Rena
authors.initials: R
authors.lastname: Nishizawa
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hisaichi
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Chiaki
authors.initials: C
authors.lastname: Minamoto
authors.forename: Hiromu
authors.initials: H
authors.lastname: Habashita
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takaoka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
authors.forename: Shiro
authors.initials: S
authors.lastname: Shibayama
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tada
authors.forename: Kenji
authors.initials: K
authors.lastname: Sagawa
authors.forename: Daikichi
authors.initials: D
authors.lastname: Fukushima
authors.forename: Kenji
authors.initials: K
authors.lastname: Maeda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007536:Isomerism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding; D051381:Rats
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D007202:Indicators and Reagents; D019402:Macrophage Inflammatory Proteins