2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors.
The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNs chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.
Dompé Research and Development, Dompé S.p.A., via Campo di Pile, 67100, L'Aquila, Italy. marcello.allegretti@dompe.it
Marcello
M
Allegretti
Riccardo
R
Bertini
Maria Candida
MC
Cesta
Cinzia
C
Bizzarri
Rosa
R
Di Bitondo
Vito
V
Di Cioccio
Emanuela
E
Galliera
Valerio
V
Berdini
Alessandra
A
Topai
Giuseppe
G
Zampella
Vincenzo
V
Russo
Nicoletta
N
Di Bello
Giuseppe
G
Nano
Luca
L
Nicolini
Massimo
M
Locati
Piercarlo
P
Fantucci
Saverio
S
Florio
Francesco
F
Colotta
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D005260:Female; D006801:Humans; D007660:Ketoprofen / Q000494:pharmacology; D008024:Ligands; D008223:Lymphoma; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D019743:Chemokines, CXC; D008024:Ligands; D011422:Propionates; D023062:Receptors, Interleukin-8A; D011994:Recombinant Proteins; D007660:Ketoprofen