Identification of novel non-peptide CXCR4 antagonists by ligand-based design approach.
The design and synthesis of novel non-peptide CXCR4 antagonists is described. The peptide backbone of highly potent cyclic peptide-based CXCR4 antagonists was entirely replaced by an indole framework, which was expected to reproduce the disposition of the key pharmacophores consistent with those of potential bioactive conformations of the original peptides. A structure-activity relationship study on a series of modified indoles identified novel small-molecule antagonists having three pharmacophore functional groups through the appropriate linkers.
Ueda
Satoshi
S
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Kato
Manabu
M
Inuki
Shinsuke
S
Ohno
Hiroaki
H
Evans
Barry
B
Wang
Zi-xuan
ZX
Peiper
Stephen C
SC
Izumi
Kazuki
K
Kodama
Eiichi
E
Matsuoka
Masao
M
Nagasawa
Hideko
H
Oishi
Shinya
S
Fujii
Nobutaka
N
D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000378:metabolism
D018925:Chemokines; D008024:Ligands; D010455:Peptides; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4