Technology
Disease Activated CNS Therapeutics
Safe and effective medicines are needed by millions of patients who have, or are at high risk for, serious diseases of the central nervous system. Many individuals are unable to get relief from neuropathic pain and those who do must frequently tolerate profound, undesirable side effects. No approved drugs offer effective neuroprotection against damage caused by ischemic injury to the brain. Similarly, there is a need for drugs that offer symptomatic relief from and halt the progression of neurodegenerative diseases such as Parkinson's and Alzheimer's.
A substantial body of data supports the expectation that a safe, potent, N-methyl-D-aspartate receptor (NMDAR) blocker would confer neuroprotection in ischemia and offer symptomatic relief from pain and improve symptoms for Parkinson's patients. Recognition of the therapeutic benefits of NMDAR modulation motivated the pharmaceutical industry to develop several generations of NMDAR blockers. Unfortunately, to date, most NMDAR antagonists brought into clinical development have failed as a result of unacceptable side effects at dose levels required for efficacy. Insights gained over years of basic research have enabled NeurOp scientists to develop a new generation of NMDAR antagonists that engage known therapeutic effects of NMDAR blockade in a much safer, disease-activated manner. NeurOp compounds offer an unprecedented opportunity to improve the safety profile of NMDAR blockers without compromising therapeutic efficacy.
Three factors underpin the novel disease - activated mechanism of action and improved performance of NeurOp compounds:
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NMDAR activity is modulated by extracellular pH. When proton concentration increases above normal physiologic levels, NMDAR are inhibited.
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Focal acidification (increase of proton concentration or decrease in pH) occurs in ischemia, neuropathic pain and other conditions characterized by rapidly firing neurons.
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NeurOp has designed subunit selective NMDAR antagonists with potency that is significantly enhanced at the acidic pH characteristic of ischemic tissue and rapidly firing neurons such as occurs in neuropathic pain.
Therapeutic Effect When and Where It Is Needed
NeurOp's compounds have minimal activity in healthy (normal pH) tissue but are "turned on" and become potent NMDAR antagonists when needed in regions of low pH caused by focal ischemia or rapid neuronal firing. Additional selectivity is achieved by binding only NMDAR containing the NR2B subunit as noncompetitive, allosteric antagonists. This offers regional selectivity and also preserves some NMDA receptor activity, as opposed to a complete antagonism caused by many previous generation antagonists.
NeurOp's most promising compounds are up to 60-fold more potent at pH 6.9 than at pH 7.6 in protecting neurons from glutamate-induced cell death in vitro, show good efficacy in the in vivo models tested and show high margins of safety.
Selectivity in Ischemia and Neuropathic Pain
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Ischemia Ischemia disrupts ionic balance in affected tissue. Increases in lactic acid, PCO2 and a rise in H+ ions contribute to focal acidification. Acidic conditions (low pH) engage the neuroprotective mechanisms of NeurOp's compounds. Data from animal models of stroke reveal that NeurOp compounds provide therapeutic benefit selectively, precisely when and where needed in ischemic tissue. |
Neuropathic pain NMDAR stimulation is linked to sensitization of dorsal horn neurons and hyperalgesia. Rapidly firing neurons can lead to reductions in interstitial pH. NeurOp's pH sensitive compounds display superior efficacy compared to non-pH sensitive compounds in models of neuropathic pain. |
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