The goal of this Phase I STTR project is to establish the feasibility of developing a small-molecule therapeutic agent designed to prevent rhabdomyolysis-induced renal failure. Rhabdomyolysis accounts for 7% to 10% of cases of renal failure in the US. Rhabdomyolysis results from muscle injury that leads to the release of myoglobin, which is then deposited in the kidney. Acute renal injury and renal failure results. Often caused by crush injuries such as those that occur with earthquakes, explosive injuries (especially to military personnel) and other trauma, rhabdomyolysis also can result from hyperthermia, seizures, muscle ischemia, coma, or statin-induced myopathy. No effective means currently exist to prevent the kidney failure that results from rhabdomyolysis. Myoglobin deposited in the kidney undergoes redox cycling, generating radicals that produce lipid peroxidation-the products of which cause vasoconstriction and tubular necrosis. Consequently, the VDDI STTR team, which includes experts from Vanderbilt University, has designed a project based on strong preliminary data that is focused on taking the first steps toward preventing the severe damage that results from rhabdomyolysis. During preliminary work we were able to demonstrate that acetaminophen inhibited the cyclooxygenase enzymes by reducing the peroxidase radicals required for their catalytic activity. We consequently found that acetaminophen also reduces the radicals generated by redox cycling of many hemeprotein peroxidases, including myoglobin. This led to the discovery that acetaminophen prevents the development of acute renal failure in a rat model of rhabdomyolysis. Because the intrinsic hepatotoxicity associated with acetaminophen limits its utility, we initiated a discovery program that yielded compounds which, like acetaminophen, inhibit the lipid peroxidation resulting from redox cycling of myoglobin but have structural differences that suggest they would not be metabolized to the type of electrophilic metabolites responsible for acetaminophen-induced hepatotoxicity. Three patent-pending compounds originating from 3 structurally distinct series have emerged from this process that are potent inhibitors of myoglobin-induced lipid peroxidation and are not cytotoxic in vitro. For this Phase I STTR project we propose to 1) determine whether these compounds are free of drug class-induced hepatotoxicity, and 2) evaluate them for efficacy in the rat model of rhabdomyolysis in comparison with acetaminophen. As a basis for these studies and for translation to clinical dosing and assessment, the metabolism and pharmacokinetics of the compounds will be characterized in multiple species. A lead compound will then be selected for follow- on preclinical development, as required by STTR solicitation PA-14-054. Phase I success will lead to a larger Phase II project focused on the studies needed to support an IND filing and ultimate commercialization of this new "orphan" treatment for rhabdomyolysis-along with commercial applications for ischemia-reperfusion myocardial injury, surgical or hemohorragic stroke, acute Sickle Cell Crisis, and many others.
Public Health Relevance Statement: Public Health Relevance: Kidney failure frequently results from major injuries to muscles, including those that occur with crush injuries such as those resulting from earthquakes, explosive trauma to military personnel, and vehicular trauma-as well as muscle injury from drugs, hyperthermia, coma and seizures. No effective treatments are available to prevent the severe kidney damage that results from the chain of events that leads to up to 10% of the kidney failure occurring in the U.S. each year. The aim of the proposed research is to develop small-molecule therapeutic agents that can prevent the acute kidney injury and kidney failure caused by major muscle injury.
Project Terms: Accounting; Acetaminophen; Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; acute stroke; Address; Affect; analog; Animals; base; Blood Circulation; Caring; Clinical; Coma; combat; commercial application; commercialization; comparative efficacy; cost; Crush Injury; cytotoxic; cytotoxicity; Data; Deposition; design; Development; Dose; Drug Formulations; Drug Kinetics; Earthquakes; effective therapy; efficacy testing; electron donor; Electrons; Enzymes; Event; Explosion; F2-Isoprostanes; Goals; Hemeproteins; Hepatotoxicity; Hospitalization; Human; Hyperthermia; In Vitro; in vitro Assay; in vivo; inhibitor/antagonist; Injury; Investigation; Ischemia; Kidney; Kidney Failure; Lead; Legal patent; Length; Life; Lipid Peroxidation; Liver; Liver Failure; Measures; meetings; metabolic abnormality assessment; Metabolism; Methodology; Methods; Military Personnel; Modeling; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Muscle; Myocardial Reperfusion Injury; Myoglobin; Myopathy; National Institute of Diabetes and Digestive and Kidney Diseases; Operative Surgical Procedures; Orphan; Orphan Drugs; Oxidation-Reduction; Peroxidases; Pharmaceutical Preparations; Phase; pre-clinical; preclinical study; prevent; Prevention; Process; programs; Prostaglandin-Endoperoxide Synthase; public health relevance; Rattus; Renal Blood Flow; Research; Rhabdomyolysis; Risk; Rodent; Safety; scaffold; Seizures; Series; sickle cell crisis; Small Business Technology Transfer Research; small molecule; success; Synthesis Chemistry; Testing; Therapeutic Agents; Toxicokinetics; Translations; Trauma; tubular necrosis; United States; Universities; Vascular constriction (function); Vasoconstrictor Agents; vehicular accident; Work
