Discovery of a potent and selective alpha v beta 3 integrin antagonist with strong inhibitory activity against neointima formation in rat balloon injury model

Seiji Iwama; Tomoko Kitano; Fumiyo Fukuya; Yayoi Honda; Yuji Sato; Mitsue Notake; Toshiya Morie

doi:10.1016/j.bmcl.2004.02.075

Discovery of a potent and selective alpha v beta 3 integrin antagonist with strong inhibitory activity against neointima formation in rat balloon injury model

Bioorg Med Chem Lett. 2004 May 17;14(10):2567-70. doi: 10.1016/j.bmcl.2004.02.075.

Authors

Seiji Iwama¹, Tomoko Kitano, Fumiyo Fukuya, Yayoi Honda, Yuji Sato, Mitsue Notake, Toshiya Morie

Affiliation

¹ Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan. seiji-iwama@dainippon-pharm.co.jp

PMID: 15109653
DOI: 10.1016/j.bmcl.2004.02.075

Abstract

A new series of phenylpiperazine-based derivatives with strong antagonistic activity for alpha v beta 3 integrin were synthesized. Of these derivatives, the fluorine-substituted compound 8 showed strong inhibitory activity and high selectivity for alpha v beta 3 integrin receptor (IC(50) = 0.055 nM). In vivo evaluation of the antistenotic effects of 8 indicated that this compound significantly inhibits neointima formation in rat balloon injury model.

MeSH terms

Angioplasty, Balloon / adverse effects*
Animals
Carotid Arteries / drug effects
Constriction, Pathologic / drug therapy
Dose-Response Relationship, Drug
Inhibitory Concentration 50
Integrin alphaVbeta3 / antagonists & inhibitors*
Models, Animal
Muscle, Smooth, Vascular / cytology
Muscle, Smooth, Vascular / drug effects
Piperazines / blood
Piperazines / chemical synthesis
Piperazines / therapeutic use*
Rats
Tunica Intima / drug effects*
Tunica Intima / growth & development

Substances

Integrin alphaVbeta3
Piperazines
phenylpiperazine