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.
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Satoshi
S
Ueda
Manabu
M
Kato
Shinsuke
S
Inuki
Hiroaki
H
Ohno
Barry
B
Evans
Zi-xuan
ZX
Wang
Stephen C
SC
Peiper
Kazuki
K
Izumi
Eiichi
E
Kodama
Masao
M
Matsuoka
Hideko
H
Nagasawa
Shinya
S
Oishi
Nobutaka
N
Fujii
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