SBIR-STTR Award

Direct to Phase II

This application, “Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics”, addresses the critical need for more effective medications to treat chronic neuropathic pain. Pain is responsible for more encounters with the health care system than any other single cause, yet treatment options for neuropathic pain have limited efficacy and carry a high risk for side effects, including opioid addiction. These factors add an additional $560-635 billion annually to an already strained United States health care system. Glutamate activation of N-methyl-D-aspartate (NMDA) receptors mediates central nervous system (CNS) sensitization, which is implicated in the development and maintenance of neuropathic pain. NMDA-mediated central sensitization depends on formation of a multi-protein cascade complex at the receptor consisting of the NMDA receptor bound to the scaffolding protein, postsynaptic density protein 95 (PSD95), and recruitment of neuronal nitric oxide synthase (nNOS). By bringing these proteins close together, multiple signaling cascades are activated leading to neural network reorganization (plasticity) and neuronal cell death. Small molecules and cell penetrating peptides that disrupt this complex act as effective analgesics in preclinical animal models with better side effect profiles than non-selective NMDA receptor antagonists and NOS inhibitors. Our team, the first to publish a small molecule targeting this complex, IC87201, demonstrated its efficacy in preclinical pain models. A similar small molecule, ZL006, is effective in preclinical stroke models. We designed and synthesized a unique and novel set of IC87201 and ZL006 analogs, advancing one molecule into IND-enabling studies for post- traumatic stress disorder. After identifying concerns with the candidate molecule, we systematically redesigned it resulting in a new set of molecules. Further funding is needed to improve on these molecules prior to advancing them toward new IND-enabling studies. Importantly, advanced toxicology studies with the candidate molecule suggest a low risk of target specific side effects and predict an excellent therapeutic index for compounds with acceptable activity and drug-like properties. In this SBIR Phase I/II fast track application, Anagin, in concert with our collaborators and the Blueprint Neurotherapeutics Network, will design and test molecules for improved drug- like properties, confirm target engagement in in vitro and ex vivo assays, demonstrate efficacy in preclinical pain models and establish a therapeutic margin using behavioral models. We will advance a new clinical candidate molecule through IND-enabling studies. Compounds that do not meet our set criteria will not be advanced. At the conclusion of these studies, we will have a new clinical candidate thoroughly interrogated and poised for testing in clinical trials for chronic pain. Data summarized in this proposal strongly suggests that our approach will yield effective analgesics with better therapeutic indices than other compounds in development or the clinic. These compounds are likely to be useful in many other glutamate-driven CNS diseases. Public Health Relevance Statement Project Narrative Chronic pain is a major health crisis for millions of Americans in part due to ineffective treatments with significant side effects. Our non-opioid approach targets a specific pathway which we believe will lead to new drugs that are safe and effective. We have assembled a team of highly experienced researchers to solve this difficult problem and advance these new compounds toward clinical trials.

Project Terms:
Affect ; Analgesics ; Analgesic Agents ; Analgesic Drugs ; Analgesic Preparation ; Anodynes ; Antinociceptive Agents ; Antinociceptive Drugs ; pain killer ; pain medication ; pain reliever ; painkiller ; inhibitor/antagonist ; inhibitor ; Non-Steroidal Anti-Inflammatory Agents ; NSAIDs ; Non Steroidal Antiinflammatory Agents ; Nonsteroidal Anti-Inflammatory Agents ; Nonsteroidal Antiinflammatory Agents ; Nonsteroidal Antiinflammatory Drug ; non-steroidal anti-inflammatory drugs ; non-steroidal antiinflammatory drugs ; nonsteroidal anti-inflammatory drugs ; Antiepileptic Agents ; Anti-epileptic ; Antiepileptic Drugs ; Antiepileptics ; anti-epileptic agents ; anti-epileptic drugs ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Brain ; Brain Nervous System ; Encephalon ; Cells ; Cell Body ; Central Nervous System Diseases ; CNS Diseases ; CNS disorder ; Central Nervous System Disorders ; Chromosome abnormality ; Aberrant Chromosome ; Chromosomal Aberrations ; Chromosomal Abnormalities ; Chromosomal Alterations ; Chromosome Aberrations ; Chromosome Alterations ; Chromosome Anomalies ; Cytogenetic Aberrations ; Cytogenetic Abnormalities ; chromosomal defect ; chromosome defect ; Clinical Trials ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Glutamates ; L-Glutamate ; glutamatergic ; Health ; Healthcare Systems ; Health Care Systems ; In Vitro ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Literature ; Maintenance ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Pain ; Painful ; Pathologic Processes ; Pathological Processes ; Peptides ; Proteins ; Publishing ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Research Personnel ; Investigators ; Researchers ; Risk ; Safety ; Signal Pathway ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Specificity ; Steroids ; Steroid Compound ; Post-Traumatic Stress Disorders ; PTSD ; Post-Traumatic Neuroses ; Posttraumatic Neuroses ; Posttraumatic Stress Disorders ; post-trauma stress disorder ; posttrauma stress disorder ; traumatic neurosis ; Stroke ; Apoplexy ; Brain Vascular Accident ; Cerebral Stroke ; Cerebrovascular Apoplexy ; Cerebrovascular Stroke ; brain attack ; cerebral vascular accident ; cerebrovascular accident ; Testing ; Toxicology ; Triage ; United States ; Work ; gabapentin ; Neurontin ; postsynaptic density protein ; N-Methylaspartate ; N Methyl D aspartic Acid ; N methyl D aspartate ; N-Methyl-D-aspartate ; NMDA ; N-Methyl-D-Aspartate Receptors ; N-Methylaspartate Receptors ; NMDA Receptor-Ionophore Complex ; NMDA Receptors ; Mediating ; chronic pain ; improved ; Clinical ; Phase ; Biological ; Series ; Chemicals ; Lesion ; Hepatotoxicity ; Hepatotoxic effect ; Liver Toxicity ; Toxic effect on liver cells ; hepatic toxicity ; hepatoxicity ; Opioid ; Opiates ; non-opioid analgesic ; non-narcotic analgesic ; non-opiate analgesic ; non-opioid ; non-opioid therapeutics ; nonnarcotic analgesics ; nonopiate analgesic ; nonopioid ; nonopioid analgesics ; analog ; Funding ; No-Observed-Adverse-Effect Level ; NOAEL ; Therapeutic ; tool ; Life ; Complex ; Oral ; Clinic ; respiratory ; Opiate Dependence ; opioid addiction ; opioid dependence ; opioid dependent ; Opiate Addiction ; Adverse reactions ; American ; experience ; membrane structure ; Membrane ; Receptor Protein ; receptor ; receptor bound ; receptor binding ; functional group ; genotoxicity ; NMDA receptor antagonist ; hazard ; nerve cell death ; nerve cell loss ; neuron cell death ; neuron cell loss ; neuron death ; neuronal cell death ; neuronal cell loss ; neuronal death ; neuronal loss ; neuron loss ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; 3-isobutyl GABA ; pregabalin ; BNOS ; NC-NOS ; NNOS ; NOS 1 protein ; NOS type I ; NOS1 protein ; Neural Constitutive Nitric Oxide Synthase ; brain nitric oxide synthase ; nNOS enzyme ; neuronal NOS ; neuronal form of nitric oxide synthase ; neuronal nitric oxide synthase ; nitric oxide synthase 1 ; Nitric Oxide Synthase Type I ; Structure ; Therapeutic Index ; novel ; Glucuronides ; neuropsychiatric ; neuropsychiatry ; Property ; protein protein interaction ; Brain Trauma ; traumatic brain damage ; Traumatic Brain Injury ; Adverse effects ; CNS Nervous System ; Central Nervous System ; Neuraxis ; small molecule ; Address ; Dose ; Data ; Preclinical Models ; Pre-Clinical Model ; Receptor Activation ; Receptor Signaling ; in vitro Assay ; in vivo ; Scaffolding Protein ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Validation ; Pathologic ; Process ; socioeconomics ; socio-economic ; socio-economically ; socioeconomically ; Development ; developmental ; Behavioral ; safety study ; Pathway interactions ; pathway ; pre-clinical ; preclinical ; painful neuropathy ; neuropathic pain ; Behavioral Model ; design ; designing ; chronic neuropathic pain ; central sensitization ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; addiction ; addictive disorder ; high risk ; good laboratory practice ; phase 1 study ; Phase I Study ; Drug Targeting ; ineffective therapies ; ineffective treatment ; patient subsets ; patient subgroups ; patient subpopulations ; patient subtypes ; health care availability ; access to health care ; access to healthcare ; accessibility of health care ; accessibility to health care ; accessibility to healthcare ; health care access ; health care service access ; health care service availability ; healthcare access ; healthcare accessibility ; healthcare availability ; healthcare service access ; healthcare service availability ; clinical candidate ; opioid epidemic ; opiate crisis ; opioid crisis ; recruit ; pain model ; lead optimization ; stroke model ; neural network ; side effect ; cost estimate ; cost estimation ;