Abstract
Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure-activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model.
MeSH terms
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Administration, Oral
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Animals
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Arthritis, Experimental / chemically induced
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Arthritis, Experimental / drug therapy*
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Benzyl Compounds / chemistry
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Benzyl Compounds / pharmacology*
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Binding Sites
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Collagen
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Cyclobutanes / chemistry
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Cyclobutanes / pharmacology*
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Disease Models, Animal
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Drug Design
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Male
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Mice
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Mice, Inbred BALB C
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Receptors, CCR1
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Receptors, Chemokine / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione
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Benzyl Compounds
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Ccr1 protein, mouse
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Cyclobutanes
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Receptors, CCR1
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Receptors, Chemokine
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Collagen