Abstract
The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Drug Evaluation, Preclinical
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Humans
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Naphthalenes / chemical synthesis
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Naphthalenes / chemistry
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Naphthalenes / metabolism
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Proline / chemistry
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Protein Binding
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Pyrrolidines / chemical synthesis
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Pyrrolidines / chemistry
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Pyrrolidines / metabolism
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Receptors, CCR3 / antagonists & inhibitors*
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Receptors, CCR3 / metabolism
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Structure-Activity Relationship
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Urea / analogs & derivatives*
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Urea / chemical synthesis
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Urea / metabolism
Substances
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(S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo(3.2.1)octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide
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Naphthalenes
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Pyrrolidines
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Receptors, CCR3
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Urea
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Proline