Abstract
A series of substituted dipiperidine compounds have been synthesized and identified as selective CCR2 antagonists. Combining the most favorable substituents led to the discovery of remarkably potent CCR2 antagonists displaying IC50 values in the nanomolar range. Compound 7a had outstanding selectivity over CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, and CCR8 and showed excellent efficacy in adjuvant-induced arthritis model, collagen-induced arthritis model, and allergic asthma model.
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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Arthritis, Experimental / drug therapy
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Asthma / drug therapy
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Cell Line
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Chemotaxis / drug effects
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Crystallography, X-Ray
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Humans
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Male
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Mice
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Rats
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Rats, Inbred Lew
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Receptors, CCR2 / antagonists & inhibitors*
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Receptors, CCR2 / chemistry
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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CCR2 protein, human
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Ccr2 protein, mouse
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Ccr2 protein, rat
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Piperidines
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Receptors, CCR2