Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Chemotaxis, Leukocyte
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Dinoprostone / biosynthesis
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Humans
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Interleukin-8 / antagonists & inhibitors*
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / physiology
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / metabolism
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Mesylates / chemical synthesis*
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Mesylates / chemistry
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Mesylates / pharmacology
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Mice
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Models, Molecular
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Mutation
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Phenylpropionates / chemical synthesis*
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Phenylpropionates / chemistry
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Phenylpropionates / pharmacology
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Propionates / chemical synthesis*
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Propionates / pharmacokinetics
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Propionates / pharmacology
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Receptors, Interleukin-8A / antagonists & inhibitors*
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Receptors, Interleukin-8A / genetics
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Receptors, Interleukin-8B / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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2-((4-trifluoromethylsulfonyloxy)phenyl)propanamide
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2-(4-(trifluoromethylsulfonyloxy)phenyl)propanoic acid
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4-(1-methyl-2-oxo-2-((4-(trifluoromethyl)-1,3-thiazol-2-yl)amino)ethyl)phenyl trifluoromethanesulfonate
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Anti-Inflammatory Agents, Non-Steroidal
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Interleukin-8
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Mesylates
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Phenylpropionates
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Propionates
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Receptors, Interleukin-8A
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Receptors, Interleukin-8B
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Dinoprostone