Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part 2: Synthesis of potent αvβ3IIbβ3 dual antagonists

Minoru Ishikawa, Dai Kubota, Mikio Yamamoto, Chizuko Kuroda, Maki Iguchi, Akihiro Koyanagi, Shoichi Murakami, Keiichi Ajito

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

We synthesized 4-aminopiperidine derivatives of our prototype integrin αvβ3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure-activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for αvβ 3 receptor binding activity. Some of these compounds are novel and potent αvβ3IIbβ 3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile.

Original languageEnglish
Pages (from-to)2109-2130
Number of pages22
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number7
DOIs
Publication statusPublished - 2006 Apr 1

Keywords

  • 4-Aminopiperidine derivatives
  • Acute ischemic disease
  • Integrin αβ antagonist
  • Integrin αβ antagonist

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