Abstract
We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 μg/mL; JP2, 462 μg/mL). Furthermore, this compound showed good oral bioavailability (F=54%) in monkeys.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Anti-Inflammatory Agents / administration & dosage
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / therapeutic use*
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Asthma / drug therapy*
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Asthma / immunology
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Biological Availability
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Bronchi / drug effects
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Bronchi / immunology
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Cell Line
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Cyclohexanecarboxylic Acids / administration & dosage
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Cyclohexanecarboxylic Acids / chemistry*
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Cyclohexanecarboxylic Acids / pharmacokinetics
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Cyclohexanecarboxylic Acids / therapeutic use*
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Eosinophils / drug effects
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Eosinophils / immunology
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Female
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Haplorhini
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Humans
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Integrin alpha4beta1 / antagonists & inhibitors*
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Integrin alpha4beta1 / immunology
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Mice
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Mice, Inbred BALB C
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Pyrrolidines / administration & dosage
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / therapeutic use
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Solubility
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Water / chemistry
Substances
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Anti-Inflammatory Agents
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Cyclohexanecarboxylic Acids
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Integrin alpha4beta1
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Pyrrolidines
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Water
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cyclohexanecarboxylic acid
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pyrrolidine