Abstract
The identification, optimization, and structure-activity relationship (SAR) of small-molecule CCR4 antagonists is described. An initial screening hit with micromolar potency was identified that was optimized to sub-micromolar binding potency by enantiomer resolution, halogenation of the naphthalene ring, and extension of the alkyl chain linker between the central piperidine ring and the terminal aryl group. An antagonist was identified that showed good cross-reactivity against the mouse receptor and inhibited CCR4-based cell recruitment in dose-dependent fashion.
MeSH terms
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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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Mice
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Mice, Inbred BALB C
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Naphthalenes / chemical synthesis
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Naphthalenes / chemistry*
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Naphthalenes / pharmacology*
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Receptors, CCR4
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Receptors, Chemokine / antagonists & inhibitors*
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Ccr4 protein, mouse
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Naphthalenes
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Receptors, CCR4
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Receptors, Chemokine
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Sulfonamides