Abstract
The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay. Compound 25 was identified as having the optimal balance of CXCR3 activity and pharmacokinetic properties across multiple pre-clinical species, which are reported herein.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Bleomycin / toxicity
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Chromosome Aberrations
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Cytochrome P-450 CYP3A
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Cytochrome P-450 CYP3A Inhibitors
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Dogs
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Dose-Response Relationship, Drug
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Drug Design
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Humans
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Inflammation
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Inhibitory Concentration 50
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Leukocytes / drug effects
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Macaca fascicularis
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Mice
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Models, Chemical
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Quinazolines / chemical synthesis*
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Quinazolines / pharmacology
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Quinazolinones / chemical synthesis*
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Quinazolinones / pharmacology
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Receptors, CXCR3 / antagonists & inhibitors*
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Time Factors
Substances
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8-aza-quinazolinone
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Cytochrome P-450 CYP3A Inhibitors
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Quinazolines
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Quinazolinones
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Receptors, CXCR3
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Bleomycin
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human