Novel lead compound advancement for mitigating halogen-induced mortality and morbidity.

新型先导化合物的进展可降低卤素引起的死亡率和发病率。

• 批准号: 10488567
• 负责人: Shama Ahmad
• 金额: $ 74.25万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488567
• 关键词: Acute; Adsorption; Animal Model; Animals; Antidotes; Authoritarianism; Biological; Biological Assay; Biological Availability; Biological Markers; Blood Cells; Blood Pressure; Brain; Bromine; Ca(2+)-Transporting ATPase; Calcium; Calpain; Cardiac; Cardiac Output; Cardiopulmonary; Cardiovascular system; Cells; Cessation of life; Chemicals; Chlorine; Clinical; Clinical Chemistry; Complete Blood Count; Cytoskeleton; Data; Development; Dose; Drug Design; Drug Kinetics; Epithelial; Evaluation; Excretory function; Exposure to; Formulation; Funding; Gases; Goals; Half-Life; Halogens; Heart; Heart Hypertrophy; Heart Injuries; Heart Rate; Hepatocyte; In Vitro; Individual; Industrialization; Inhalation; Injury; Intramuscular; Kidney; Lead; Liver; Lung; Maximum Tolerated Dose; Mediating; Metabolism; Modeling; Molecular Target; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardium; Oral; Oryctolagus cuniculus; Oxygen; Paramedical Personnel; Parents; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiologic intraventricular pressure; Plasma; Property; Proteolysis; Publishing; Pulmonary Edema; Rattus; Research; Reticulum; Route; Safety; Site; Soldier; Solubility; Spleen; Structure; Structure-Activity Relationship; Survivors; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; United States National Institutes of Health; Validation; Vendor; World War I; analog; animal rule; base; calpain inhibitor; chemical threat; design; effective therapy; efficacy study; heart function; heart preservation; hemodynamics; improved; in vitro activity; in vivo; intraperitoneal; kidney cell; lead optimization; lung histology; lung injury; molecular targeted therapies; mortality; novel; novel lead compound; programs; respiratory; response; safety study; subcutaneous; therapeutic development; therapeutic lead compound; therapeutically effective; weapons

Summary: Chlorine and bromine (Cl2 and Br2) are highly reactive and extremely toxic halogen gases that cause debilitating cardiopulmonary injury and death. Research from our previously funded ‘Identification of Therapeutic Lead Compounds U01’ provided published and preliminary data that identified calpain inhibitor (CI) as highly efficacious and safe antidote for Br2 inhalation-induced cardiopulmonary injury and mortality. These studies were carried out in our unique halogen exposure facility and the discovery of the mitigating agent was made possible by the development of the Cl2/Br2 exposure-induced rat model of acute cardiopulmonary damage and mortality. Using the whole body Br2 exposure rat model we demonstrated that the therapeutic action of CIs is caused by reduction in Br2 induced calpain activity, reduction of proteolysis of the myocardium and preservation of cardiac function leading to decreased mortality. Calpains (calcium dependent proteases) are activated by Br2/Br2 reactant-induced loss of cardiac sarcoendoplasmic reticulum Ca2+ ATPase, SERCA activity and subsequent catastrophic cytosolic Ca2+ overload. Intraperitoneal administration of a CI (that was selected from several commercially available CIs based on an ex-vivo high-throuput evaluation of cardiac calpain inhibition) 1h after Br2 exposure significantly mitigated acute increase in cardiac calpain activity, decreased Br2-induced mortality. Administration of CI significantly improved the clinical scores, heart rate and oxygen saturation. Br2-induced pulmonary edema and cardiac hypertrophy was also reduced. Several cardiovascular parameters such as blood pressure, ventricular pressure, cardiac output and other diastolic and systolic heart functions were improved in Br2-exposed animals after CI treatment. We have also initiated the studies on its various structural analogs. These structures were characterized for their improved solubility, bioavailability and stability. Preliminary data for their activity and cellular toxicity was also evaluated. Thus, as mentioned in the CounterACT FOA we provided validation of molecular targets for therapeutic development, proof of in vitro activity of the lead compound, preliminary in vivo proof-of-concept efficacy data, and preliminary adsorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) evaluations. Therefore, this lead compound ‘calpain inhibitor’ is now ready for optimization and we will also evaluate ADME/safety profile of the CI and its most effective analog. Optimization of CI/analog dose and delivery in a large animal model of halogen-induced cardiopulmonary injury will also be performed. These studies will allow the lead compound to move forward and help design the pivotal studies needed for regulatory FDA approval of CI under the animal rule.

摘要：氯和溴（Cl2和Br2）是高活性和剧毒的卤素气体