Synthesis of potent αvβ3IIbβ3 dual antagonists tricyclic pharmacophore-based molecules and their selectivity control

Minoru Ishikawa, Dai Kubota, Keiichi Ajito

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


The blockade αIIbβ3 binding to fibrinogen is known to provide a potent antiplatelet activity. We have focused on the adhesion and migration of integrin αvβ3 in vascular smooth muscle cells and leucocytes. An injectable α vβ3IIbβ3 dual antagonist would be a novel drug candidate for acute ischemic diseases. For the molecular design of novel non-peptide integrin αvβ 3 antagonists, we focused on spatial screening and mimetics of the RGD tripeptide, which was a key recognition site. The first piperazine analogue (4) exhibited strong αIIbβ3 activity, and replacement of piperazine by 4-aminopiperidine afforded the α vβ3IIbβ3 dual antagonist (30). Paying attention to enhancement of activity and improvement of solubility, optimization of 30 gave some preliminary candidates modified at the central aromatic or the C-terminus. Backup compounds possessing the (3S)-aminopiperidine moiety with further improvement of solubility were synthesized. These preliminary candidates exhibited preferable ADME in rats, and some of them showed acceptable water solubility, which did not provide detectable toxicity in vitro or in mice. We also generated α vβ3 selective antagonists with tricyclic pharmacophore, in order to prove that in vivo efficacy of the dual antagonist was superior to that of the αvβ3 selective antagonist. Finally, excellent in vivo efficacy of the candidate (81) was demonstrated in both canine ACS and PTCA models by independent groups. Regarding development of 81, a partnership was established in 2006, and a clinical trial of 81 is now being prepared in the US and Canada. The selection of an integrin research program, strategies for competing with big pharmaceutical companies, and speedy medicinal chemistry are also described.

Original languageEnglish
Pages (from-to)1093-1104
Number of pages12
JournalYuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
Issue number11
Publication statusPublished - 2008 Nov


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