Optimization of CXCR1/2 antagonist SX-576 for the treatment of BPD and COPD

CXCR1/2拮抗剂SX-576治疗BPD和COPD的优化

基本信息

批准号：
8199990
负责人：
DEAN YOSHIMASA MAEDA
金额：
$ 81.14万
依托单位：
SYNTRIX BIOSYSTEMS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-01-17 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8199990
关键词：
Acute Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Bioavailable Biological Availability Boronic Acids Bronchopulmonary Dysplasia CXCL1 gene Canis familiaris Chemical Structure Chemistry Chemotaxis Chronic Chronic Obstructive Airway Disease Clinical Trials Contracts Development Disease Dose Drug Formulations Drug Kinetics Evaluation Exhibits Funding Future Goals Grant Human IL8RA gene IL8RB gene In Vitro Inflammation Inflammatory Inhibitory Concentration 50 Injury Interleukin-8B Receptor Investigational Drugs Investigational New Drug Application Laboratories Lead Link Lung Mediating Metabolism Mission Modeling Modification Neutrophil Infiltration Nitrogen Oral Patients Pharmaceutical Preparations Pharmacologic Substance Phase Pneumonia Preparation Procedures Process Property Public Health Rattus Research Contracts Risk Rodent Safety Site Small Business Innovation Research Grant Societies Solubility Staging Structure Sulfur Tablets Therapeutic Toxicokinetics Toxicology United States National Institutes of Health analog aqueous burden of illness capsule carbene chemokine expectation functional group good laboratory practice human subject improved in vivo inhibitor/antagonist inorganic phosphate migration neutrophil novel pre-clinical release of sequestered calcium ion into cytoplasm research clinical testing small molecule stability testing

项目摘要

DESCRIPTION (provided by applicant): SX-576 is a small molecule CXCR1/2 antagonist that potently blocks the migration of neutrophils to sites of injury and/or inflammation. SX-576 is being developed as a potential therapeutic for the treatment of pulmonary inflammatory diseases, such as bronchopulmonary dysplasia (BPD) and chronic obstructive pulmonary disease (COPD). In this study, the pharmacokinetic properties of SX-576 will be optimized through chemical structure modification and formulation development. The new analogs and formulations will be evaluated for activity in isolated human neutrophils, and for improved oral bioavailability in pharmacokinetic studies. A preclinical candidate will be selected and evaluated in a rat model of pulmonary inflammation. A process for the large scale preparation and formulation of the preclinical lead compound will be developed, followed by toxicology studies to assess its safety. At the conclusion of this study, the necessary information for an Investigational New Drug (IND) application for clinical evaluation in humans will have been collected. In summary, the successful completion of this study would advance a potential new treatment for pulmonary inflammatory diseases, thereby advancing the mission of the NIH to lessen the burdens of illness in our society. PUBLIC HEALTH RELEVANCE: Pulmonary inflammatory diseases such as bronchopulmonary dysplasia (BPD) and chronic obstructive pulmonary disease (COPD) affect more than 12 million people in the U.S., and represent a significant burden to public health. This Phase II competing renewal would advance a novel anti-inflammatory drug towards clinical evaluation in patients suffering from pulmonary inflammatory disease.

描述（由申请人提供）：SX-576是一个小分子CXCR1/2拮抗剂，可有效阻止中性粒细胞向损伤和/或炎症部位的迁移。 SX-576正在开发为治疗肺部炎症性疾病的潜在治疗方法，例如支气管肺发育不良（BPD）和慢性阻塞性肺疾病（COPD）。在这项研究中，SX-576的药代动力学特性将通过化学结构修饰和制剂的发展进行优化。将评估新的类似物和制剂在分离的人类嗜中性粒细胞中的活性，并在药代动力学研究中改善口服生物利用度。将在肺部炎症大鼠模型中选择并评估临床前候选者。将开发大规模制备和制定临床前铅化合物的过程，然后进行毒理学研究以评估其安全性。在本研究结束时，将收集研究新药（IND）在人类中进行临床评估的必要信息。总而言之，这项研究的成功完成将推动对肺部炎症性疾病的潜在新治疗方法，从而促进NIH的使命，以减轻我们社会的疾病负担。公共卫生相关性：肺部炎症性疾病，例如支气管肺发育不良（BPD）和慢性阻塞性肺疾病（COPD）影响了美国超过1200万人，这代表了公共卫生的重大负担。这次II期竞争的更新将使一种新型的抗炎药推向患有肺部炎症性疾病的患者的临床评估。