{"record_key":"next-generation-targeted-nitroxides","identifier":"05064","external_key":"05064","title":"Next-Generation Mitochondria-Targeted Nitroxide Compounds That Block Ferroptosis","summary":null,"url":"https://inventions.pitt.edu/technologies/next-generation-mitochondria--05064","json_url":"https://inventions.pitt.edu/technologies/next-generation-mitochondria--05064.json","object_key":"technologies","description":"This invention is a new family of small-molecule compounds that pair a radical-trapping nitroxide group with a tailored targeting fragment to protect cells from ferroptosis, an iron-dependent form of cell death driven by lipid damage. These compounds offer a new way to protect tissue in a wide range of neurodegenerative, ischemic, metabolic and inflammatory conditions in which ferroptosis contributes to disease. \nDescription\nFerroptosis occurs when lipid peroxides, which are damaging oxidized fats, build up in cell membranes. The compounds are built around a nitroxide group (2,2,6,6-tetramethylpiperidine-N-oxyl), a stable radical that neutralizes the reactive radicals that drive this chain reaction. The nitroxide is joined through an amide linkage to a short, protected amino-alkene backbone that serves as the targeting portion. The backbone carries a nitrogen-protecting acyl group, such as Boc, and a branched alkyl or fluorinated side chain. It also carries paired substituents at the carbon next to the amide, such as methyl, benzyl or cyclic groups, that tune the compound’s properties.\nThe compounds are made by asymmetric synthetic routes, which produce single-handed (enantioenriched) molecules. The chemistry gives access to many structural variants, including different substituent patterns and cis or trans double-bond geometries. The compounds can be formulated as pharmaceutical compositions in a range of dosage forms, including intravenous, oral, topical and transdermal.\nApplications\n- Neuroprotective therapeutics for neurodegenerative diseases (Alzheimer’s, Parkinson’s, Huntington’s, ALS, multiple sclerosis) and traumatic brain injury\n- Treatments for ischemic stroke and intracerebral hemorrhage\n- Organ-protective agents for acute kidney disease, liver injury and fibrosis, and ischemia/reperfusion injury\n- Therapeutics for age-related macular degeneration, diabetes and acute myeloid leukemia\n- Anti-inflammatory therapies for psoriasis, hemolytic disorders and other inflammatory diseases\nAdvantages\n- Radical-trapping nitroxide action that directly counters lipid peroxidation, the central driver of ferroptosis\n- Several analogs showed stronger protection in cell testing than the earlier benchmark compound in the same assay\n- Potent lead analogs with sub-micromolar activity (EC50 of about 173 nM, 207 nM and 576 nM for three analogs)\n- Tunable chemistry, with variable side chains, ring systems and double-bond geometry for optimizing potency and lipophilicity\n- Broad therapeutic reach across diseases in which ferroptosis contributes\nInvention Readiness\nThe compounds have been designed and synthesized across multiple analog series using asymmetric routes. In cell-based testing against erastin-induced ferroptosis in HT-1080 cells, several analogs preserved 77–85% cell activity at 1 µM, compared with 56% for the earlier benchmark compound. The most potent analogs reached EC50 values in the 170–580 nM range.\nIP Status\nhttps://patents.google.com/patent/US12486231B2","attributes":[{"key":"file_number","label":"Reference Number","values":["05064"]},{"key":"technology_type","label":"Technology Type","values":["Therapeutic Modality"]},{"key":"technology_subtype","label":"Technology Subtype","values":["Small Molecule"]},{"key":"therapeutic_areas","label":"Therapeutic Areas","values":["Neuroscience","Nephrology"]},{"key":"therapeutic_indications","label":"Therapeutic Indications","values":["Parkinson's Disease","Multiple Sclerosis (MS)","Alzheimer's Disease","Acute Kidney Injury (AKI)"]},{"key":"tags","label":"Tags","values":["Aging","Critical Care"]},{"key":"lead_inventor_name","label":"Lead Inventor","values":["Peter Wipf"]},{"key":"lead_inventor_dept","label":"Department","values":["Chemistry"]},{"key":"all_tech_innovators","label":"All Innovators","values":["Peter Wipf"]},{"key":"technology_readiness_level","label":"Technology Readiness Level","values":["2. Initial proof of concept, in-vitro"]},{"key":"date_submitted","label":"Date Submitted","values":["Jul 20, 2019"]}],"related":[]}