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

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2131-2150
Number of pages20
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number7
DOIs
Publication statusPublished - 2006 Apr 1
Externally publishedYes

Keywords

  • 3-aminopiperidine derivatives
  • Acute ischemic disease
  • Integrin αβ antagonist
  • Integrin αβ antagonist

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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