Spirodiketopiperazine-based CCR5 antagonists: Lead optimization from biologically active metabolite.
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.
Nishizawa
Rena
R
Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, Osaka 618-8585, Japan. r.nishizawa@ono.co.jp
Nishiyama
Toshihiko
T
Hisaichi
Katsuya
K
Matsunaga
Naoki
N
Minamoto
Chiaki
C
Habashita
Hiromu
H
Takaoka
Yoshikazu
Y
Toda
Masaaki
M
Shibayama
Shiro
S
Tada
Hideaki
H
Sagawa
Kenji
K
Fukushima
Daikichi
D
Maeda
Kenji
K
Mitsuya
Hiroaki
H
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
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D007202:Indicators and Reagents; D019402:Macrophage Inflammatory Proteins