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（Cl2 和 Br2）是高活性且剧毒的卤素气体，会导致我们之前资助的“治疗识别”研究。先导化合物 U01' 提供了已发表的初步数据，表明钙蛋白酶抑制剂 (CI) 具有高度这些研究是针对 Br2 吸入引起的心肺损伤和死亡的有效且安全的解毒剂。在我们独特的卤素暴露设施中进行，并使得缓解剂的发现成为可能通过开发 Cl2/Br2 暴露诱发的大鼠急性心肺损伤和死亡模型。使用全身 Br2 暴露大鼠模型，我们证明 CI 的治疗作用是由减少 Br2 诱导的钙蛋白酶活性，减少心肌蛋白水解并保护心脏导致死亡率降低的功能是钙蛋白酶（钙依赖性蛋白酶）被 Br2/Br2 激活。反应物诱导的心脏肌内质网 Ca2+ ATP 酶、SERCA 活性和随后的损失腹膜内给予CI（从几个中选择）发生灾难性的胞质Ca2+超载。市售 CI 基于心脏钙蛋白酶抑制的离体高通量评估）1 小时后 Br2 暴露显着减轻了心脏钙蛋白酶活性的急剧增加，降低了 Br2 引起的死亡率。 CI 的施用显着改善了 Br2 诱导的临床评分、心率和氧饱和度。肺水肿和心脏肥大也减少了，例如血液等一些心血管参数。血压、心室压、心输出量和其他舒张和收缩心脏功能均得到改善 CI治疗后暴露于Br2的动物我们也开始了对其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度、生物利用度和稳定性。因此，正如我们提供的 CounterACT FOA 中提到的那样，还评估了它们的活性和细胞毒性。验证治疗开发的分子靶标，证明先导化合物的体外活性，初步的体内概念验证功效数据，以及初步的吸附、分布、代谢、排泄，因此，这种先导化合物“钙蛋白酶抑制剂”现已准备就绪。优化，我们还将评估 CI 的 ADME/安全概况及其最有效的模拟优化。 CI/类似物剂量和在卤素引起的心肺损伤的大型动物模型中的递送也将是这些研究将使先导化合物取得进展并有助于设计关键研究。需要FDA根据动物规则批准CI。