Stroke and
head trauma are worldwide public health problems and leading causes of death and disability in humans, yet, no adequate neuroprotective treatment is available for
therapy.
Glutamate antagonists are considered major
drug candidates for neuroprotection in
stroke and
trauma. However,
N-methyl-D-aspartate antagonists failed clinical trials because of unacceptable side effects and short therapeutic time window. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate (
AMPA) antagonists derived from the quinoxalinedione scaffold cannot be used in humans because of their insolubility and resulting renal toxicity. Therefore, achieving water solubility of quinoxalinediones without loss of selectivity and potency profiles becomes a major challenge for medicinal chemistry. One of the major tenets in the chemistry of
glutamate antagonists is that the incorporation of
phosphonate into the
glutamate framework results in preferential
N-methyl-D-aspartate antagonism. Therefore, synthesis of
phosphonate derivatives of quinoxalinediones was not pursued because of a predicted loss of their selectivity toward
AMPA. Here, we report that introduction of a
methylphosphonate group into the quinoxalinedione skeleton leaves potency as
AMPA antagonists and selectivity for the
AMPA receptor unchanged and dramatically improves solubility. One such novel
phosphonate quinoxalinedione derivative and competitive
AMPA antagonist
ZK200775 exhibited a surprisingly long therapeutic time window of >4 h after permanent occlusion of the middle cerebral artery in rats and was devoid of renal toxicity. Furthermore,
delayed treatment with
ZK200775 commencing 2 h after onset of reperfusion in transient
middle cerebral artery occlusion resulted in a dramatic reduction of the
infarct size.
ZK200775 alleviated also both cortical and hippocampal damage induced by
head trauma in the rat. These observations suggest that
phosphonate quinoxalinedione-based
AMPA antagonists may offer new prospects for treatment of
stroke and
trauma in humans.