Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III: Synthesis of potent antagonists with αvβ3IIbβ3 dual activity and improved water solubility

Minoru Ishikawa, Yukiko Hiraiwa, Dai Kubota, Masaki Tsushima, Takashi Watanabe, Shoichi Murakami, Shokichi Ouchi, Keiichi Ajito

研究成果: Article査読

37 被引用数 (Scopus)

抄録

In order to optimize our novel integrin αvβ 3IIbβ3 dual antagonists, spatial screening at the N-terminus was performed. The αvβ 3 antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against αIIbβ 3 was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against αvβ3, and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the αvβ3 receptor were performed to confirm the SAR findings.

本文言語English
ページ(範囲)2131-2150
ページ数20
ジャーナルBioorganic and Medicinal Chemistry
14
7
DOI
出版ステータスPublished - 2006 4月 1
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子医療
  • 分子生物学
  • 薬科学
  • 創薬
  • 臨床生化学
  • 有機化学

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