Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2.
Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. A novel class of small molecular weight allosteric CXCR1 inhibitors was identified, and reparixin, the first drug candidate, is currently under clinical investigation in the prevention of ischemia/reperfusion injury in organ transplantation. Reparixin binding mode to CXCR1 has been studied and used for a computer-assisted design program of dual allosteric CXCR1 and CXCR2 inhibitors. In this paper, the results of modeling-driven SAR studies for the identification of potent dual inhibitors are discussed, and three new compounds (56, 67, and 79) sharing a common triflate moiety have been selected as potential leads with optimized pharmacokinetic characteristics.
Research Centre, Dompé pha.r.ma s.p.a., via Campo di Pile, 67100, L'Aquila, Italy.
Alessio
A
Moriconi
Maria Candida
MC
Cesta
Maria Neve
MN
Cervellera
Andrea
A
Aramini
Silvia
S
Coniglio
Sandro
S
Colagioia
Andrea Rosario
AR
Beccari
Cinzia
C
Bizzarri
Michela Rita
MR
Cavicchia
Massimo
M
Locati
Emanuela
E
Galliera
Paola
P
Di Benedetto
Paolo
P
Vigilante
Riccardo
R
Bertini
Marcello
M
Allegretti
D000494:Allosteric Regulation; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008698:Mesylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors* / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C523813:2-((4-trifluoromethylsulfonyloxy)phenyl)propanamide; C523812:2-(4-(trifluoromethylsulfonyloxy)phenyl)propanoic acid; C523833:4-(1-methyl-2-oxo-2-((4-(trifluoromethyl)-1,3-thiazol-2-yl)amino)ethyl)phenyl trifluoromethanesulfonate; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016209:Interleukin-8; D008698:Mesylates; D010666:Phenylpropionates; D011422:Propionates; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D015232:Dinoprostone