Exploration of a Series of 5-Arylidene-2-thioxoimidazolidin-4-ones as Inhibitors of the Cytolytic Protein Perforin

详细信息    查看全文

• 作者：Julie A. Spicer ; Gersande Lena ; Dani M. Lyons ; Kristiina M. Huttunen ; Christian K. Miller ; Patrick D. O鈥機onnor ; Matthew Bull ; Nuala Helsby ; Stephen M. F. Jamieson ; William A. Denny ; Annette Ciccone ; Kylie A. Browne ; Jamie A. Lopez ; Jesse Rudd-Schmidt ; Ilia Voskoboinik ; Joseph A. Trapani
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9542-9555
• 全文大小：530K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perforin. Structure鈥揳ctivity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations (鈮?.5 渭M) by surface plasmon resonance and prevented formation of perforin pores in target cells despite effective target cell engagement, as determined by calcium influx studies. Mouse PK studies of two analogues showed T_1/2 values of 1.1鈥?.2 h (dose of 5 mg/kg iv) and MTDs of 60鈥?0 mg/kg (ip).