Abstract
The evaluation of the CXCR3 antagonist AMG 487 in clinic trials was complicated due to the formation of an active metabolite. In this Letter, we will discuss the further optimization of the quinazolinone series that led to the discovery of compounds devoid of the formation of the active metabolite that was seen with AMG 487. In addition, these compounds also feature increased potency and good pharmacokinetic properties. We will also discuss the efficacy of the lead compound 34 in a mouse model of cellular recruitment induced by bleomycin.
MeSH terms
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Acetamides / pharmacology
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / pharmacokinetics
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Cell Movement
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Dogs
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Haplorhini
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Humans
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Mice
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Pyrimidinones / chemical synthesis
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Pyrimidinones / chemistry*
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Pyrimidinones / pharmacology
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Quinazolinones / chemical synthesis
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Quinazolinones / chemistry*
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Quinazolinones / pharmacokinetics
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Rats
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Receptors, CXCR3 / antagonists & inhibitors*
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Receptors, CXCR3 / metabolism
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Structure-Activity Relationship
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Sulfones / chemical synthesis
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Sulfones / chemistry*
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Sulfones / pharmacology
Substances
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Acetamides
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Anti-Inflammatory Agents
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N-(1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido(2,3-d)pyrimidin-2-yl)ethyl)-N-pyridin-3-ylmethyl-2-(4-trifluoromethoxyphenyl)acetamide
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Pyrimidinones
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Quinazolinones
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Receptors, CXCR3
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Sulfones