Chronic pain contributes to over $600 billion worth of healthcare expenditures annually, more than the yearly cost of cancer, heart disease, and diabetes combined. Neuropathic pain affects between 6 and 10% of the population and is associated with decreased quality of life and socioeconomic burdens exceeding all other chronic pain disorders. Existing neuropathic pain therapeutics lack efficacy. This has a profound influence on patient quality of life and is a source of frustration for caregivers. To develop the next generation of neuropathic pain therapeutics, new, mechanism-based agents that target specific pathways that lead to aberrant neuronal signaling must be developed. Injury to peripheral nerves activates a number of signaling pathways that contribute to pathological changes that alter the phenotype and excitability of dorsal root ganglion DRG) neurons. These signaling pathways include the mechanistic target of rapamycin mTOR) and the mitogen activated protein kinase pathways MAPK). These signaling pathways can be targeted simultaneously by activating adenosine monophosphate-activated protein kinase AMPK). In rat and mouse models of neuropathic pain AMPK activators fully reverse neuropathic mechanical and cold hypersensitivity and have disease modifying properties causing a complete reversal of signs of neuropathic pain for up to two months following cessation of treatment. Potent, drug-like activators of AMPK have not been developed for the treatment of neuropathic pain. Our goal is to develop these compounds through 3 aims. First we will use lead scaffolds with AMPK activating activity to develop novel AMPK activators with drug-like qualities and screen them for AMPK activating activity against the human recombinant kinase. We will then use an iterative, rationale drug design approach guided by in silico drug docking against the AMPK crystal structure to refine these molecules. Finally we will test select lead molecules in vivo to assess efficacy. Collectively these aims will achieve the following goals: 1) they will establish novel chemistry and enable further testing of this pharmacological mechanism for neuropathic pain; 2) they will establish an IP foundation around this mechanism and 3) they will set the stage for more extensive IND-enabling testing in Phase II.
Public Health Relevance Statement: Project Narrative NIH Phase I SBIR Proposal Company: CerSci Therapeutics PI: Scott Dax Title: Novel AMPK Activators for the treatment of neuropathic pain Neuropathic pain is an important clinical problem that creates an enormous burden for patients, their families, physicians and health-care systems. Only 50% of neuropathic patients get even 50% relief of their pain from current therapeutics; therefore, novel therapeutics for neuropathic pain are urgently needed. AMPK is a novel therapeutic target for neuropathic pain, however, potent and specific AMPK activators are not currently available for human use. Our goal is to develop first in class molecules for this mechanism for the treatment of neuropathic pain.
Project Terms: 5'-AMP-activated protein kinase; Adenosine Monophosphate; Adverse effects; Affect; Allosteric Site; AMP-activated protein kinase kinase; Animal Model; Behavioral; Binding; Biological Assay; Biology; Caregivers; Cells; Chemicals; Chemistry; chronic neuropathic pain; chronic pain; Clinical; Computer Assisted; Computer Simulation; cost; Crystallization; Crystallography; cytotoxicity; design; Development; Diabetes Mellitus; Disease; Docking; Dose; Drug Design; drug discovery; Expenditure; Family Physicians; Foundations; FRAP1 gene; Free Radicals; Frustration; Goals; Healthcare; Healthcare Systems; Heart Diseases; Human; Hybrids; Hypersensitivity; in vivo; Industry Standard; information model; Injury; Intellectual Property; Lead; Libraries; Ligands; Malignant Neoplasms; MAP Kinase Gene; Maps; Mechanics; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular Conformation; Molecular Structure; mouse model; Mus; Nerve Growth Factors; nerve injury; Neurons; Neuropathy; neurotransmission; new therapeutic target; next generation; novel; novel therapeutics; Pain; Pain Disorder; painful neuropathy; Pathologic; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System; Peroxonitrite; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Phosphotransferases; Population; positive allosteric modulator; Price; Property; Protein Dephosphorylation; Protein Kinase; prototype; Publishing; Quality of life; Rationalization; Rattus; Reaction; Recombinants; Resolution; scaffold; screening; Sensory; Series; Signal Pathway; single molecule; Site; Small Business Innovation Research Grant; small molecule libraries; socioeconomics; Source; spared nerve; Specificity; Spinal Ganglia; Structure; Study models; targeted agent; Testing; Treatment Efficacy; United States National Institutes of Health; Withholding Treatment
