1 research outputs found
Exploration of a Series of 5‑Arylidene-2-thioxoimidazolidin-4-ones as Inhibitors of the Cytolytic Protein Perforin
A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones
were
investigated as inhibitors of the lymphocyte-expressed pore-forming
protein perforin. Structure–activity 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 (≤2.5 μM) 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 <i>T</i><sub>1/2</sub> values of 1.1–1.2 h (dose of 5 mg/kg iv) and
MTDs of 60–80 mg/kg (ip)