441718-01-0Relevant academic research and scientific papers
PYRROLOBENZODIAZEPINE COMPOUNDS
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, (2015/11/24)
The invention relates to pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) of formula (I) and in particular to PBD dimers linked through the C1 position, and PBD monomers linked through the C1 position to aromatic groups, and pharmaceutically acceptable salts the
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
Setoguchi, Masaki,Iimura, Shin,Sugimoto, Yuuichi,Yoneda, Yoshiyuki,Chiba, Jun,Watanabe, Toshiyuki,Muro, Fumihito,Iigo, Yutaka,Takayama, Gensuke,Yokoyama, Mika,Taira, Tomoe,Aonuma, Misato,Takashi, Tohru,Nakayama, Atsushi,MacHinaga, Nobuo
, p. 42 - 61 (2013/02/22)
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 12.5 mg/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.
