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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。

基本信息

批准号：
10705647
负责人：
Shama Ahmad
金额：
$ 73.04万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
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/10705647
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 Endoplasmic Reticulum Epithelium 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 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 calpain inhibitor chemical threat design effective therapy efficacy evaluation efficacy study heart function heart preservation hemodynamics improved in vitro activity in vivo intraperitoneal kidney cell lead optimization lung histology lung injury meter molecular targeted therapies mortality novel novel lead compound programs respiratory response safety study subcutaneous therapeutic development therapeutic lead compound therapeutically effective weapons

项目摘要

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（Cl 2和Br 2）是高反应性和极毒的卤素气体，使人虚弱的心肺损伤和死亡。我们以前资助的“治疗性疾病的识别”研究先导化合物U 01“提供了已发表的和初步的数据，这些数据将钙蛋白酶抑制剂（CI）鉴定为高度有效和安全的解毒剂吸入溴诱导的心肺损伤和死亡率。这些研究在我们独特的卤素暴露设施中进行，并发现了缓解剂通过建立Cl 2/Br 2染毒诱导的大鼠急性心肺损伤模型及死亡率。使用全身Br 2暴露大鼠模型，我们证明了CI的治疗作用是由以下因素引起的：减少Br 2诱导的钙蛋白酶活性，减少心肌的蛋白水解和保护心脏功能，降低死亡率。钙蛋白酶（钙依赖性蛋白酶）被Br 2/Br 2激活反应诱导的心肌肌内质网Ca 2 + ATP酶、SERCA活性和随后的灾难性的胞质Ca 2+超载。腹膜内施用CI（其选自几种基于心脏钙蛋白酶抑制的离体高通量评价的市售CI）给药后1小时 Br 2暴露显著减轻了心脏钙蛋白酶活性的急性增加，降低了Br 2诱导的死亡率。给予CI显著改善了临床评分、心率和血氧饱和度。溴诱导肺水肿和心脏肥大也减少了。几个心血管参数，如血液血压，心室压，心输出量和其他舒张和收缩心脏功能得到改善， Cl处理后Br 2暴露的动物。我们还开始了对它的各种结构类似物的研究。这些结构的特征在于其改善的溶解性、生物利用度和稳定性。初步数据还评价了它们的活性和细胞毒性。因此，正如我们提供的反ACT FOA中所提到的，用于治疗开发的分子靶标的验证，先导化合物的体外活性的证明，初步体内概念验证功效数据，以及初步吸附、分布、代谢、排泄，和毒性（ADME/Tox）评价。因此，这种先导化合物“钙蛋白酶抑制剂”现在可以用于我们还将评估CI及其最有效的类似物的ADME/安全性特征。优化 CI/类似物的剂量和递送在卤素诱导的心肺损伤的大型动物模型中也将是执行。这些研究将使先导化合物向前推进，并帮助设计关键研究根据动物规则，需要FDA批准CI。