Exploration of a series of 5-arylidene-2-thioxoimidazolidin-4-ones as inhibitors of the cytolytic protein perforin.

摘要: A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors the lymphocyte-expressed pore-forming protein perforin. Structure-activity relationships explored through variation an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability resulting compounds to inhibit lytic activity both isolated perforin and delivered in situ by natural killer cells was determined. number showed excellent at concentrations that nontoxic cells, several significant improvement previous classes inhibitors, being substantially more potent soluble. Representative examples rapid reversible binding immobilized mouse low (≤2.5 μM) surface plasmon resonance prevented formation pores target despite effective cell engagement, determined calcium influx studies. Mouse PK studies two analogues T1/2 values 1.1-1.2 h (dose 5 mg/kg i.v.) MTDs 60-80 (i.p.).