Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 23, Pages 9542-9555Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm401604x
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Funding
- Wellcome Trust [092717]
- Auckland Division of the Cancer Society of New Zealand
- Academy of Finland [135439]
- Finnish Cultural Foundation
- National Health & Medical Research Council (NHMRC)
- NHMRC
- Academy of Finland (AKA) [135439, 135439] Funding Source: Academy of Finland (AKA)
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A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perform. 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 perform 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 mu 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 1.1-1.2 h (dose of 5 mg/kg iv) and MTDs of 60-80 mg/kg (ip).
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