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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.


Masaki Setoguchi, Shin Iimura, Yuuichi Sugimoto, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Fumihito Muro, Yutaka Iigo, Gensuke Takayama, Mika Yokoyama, Tomoe Taira, Misato Aonuma, Tohru Takashi, Atsushi Nakayama, Nobuo Machinaga. A novel, potent, and orally active VLA-4 antagonist with good aqueous solubility: trans-4-[1-[[2-(5-Fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl]acetyl]-(5S)-[methoxy(methyl)amino]methyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid. Bioorganic & medicinal chemistry. 2013 Jan 1;21(1):42-61

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PMID: 23218775

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