Bronchopulmonary Dysplasia Drug Therapy

支气管肺发育不良药物治疗

基本信息

批准号：
8056184
负责人：
DEAN YOSHIMASA MAEDA
金额：
$ 21.88万
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 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8056184
关键词：
Acids Adult Respiratory Distress Syndrome Affect Air Amides Anti-Inflammatory Agents Binding Binding Sites Biological Assay Blood Bronchopulmonary Dysplasia Cells Chemical Structure Chemotactic Factors Chemotaxis Computer Simulation Cyclic GMP Data Development Diffusion Disease Drug Formulations Drug Kinetics Dysbarism Elements Environmental air flow Esters Evaluation Exhibits G-Protein-Coupled Receptors Generations Glycolates Goals Growth Hepatocyte Human IL8RA gene IL8RB gene Immune system In Vitro Infant Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Injection of therapeutic agent Injury Interleukin-8 Intestinal Absorption Intestines Intravenous Investigational Drugs Investigational New Drug Application Lead Life Literature Liver Microsomes Lung Lymphoma Mechanical ventilation Mediating Metabolic Metabolism Methotrexate Modeling Modification Mus Neutrophil Infiltration Niacinamide Oncogenes Oral Oxidants Oxygen Permeability Pharmacotherapy Phase Plasma Process Prodrugs Property Psoriasis Radiolabeled Rattus Research Personnel Resistance Role Silicon Dioxide Site Small Business Innovation Research Grant Space Perception Structure of parenchyma of lung Testing Therapeutic Thymidine Kinase Toxic effect Toxicology absorption analog carboxylate cytotoxicity esterase genotoxicity improved in vivo inhibitor/antagonist lung injury migration neonate neutrophil novel pharmacophore phase 1 study pre-clinical programs radiotracer receptor release of sequestered calcium ion into cytoplasm research clinical testing research study scaffold small molecule

项目摘要

DESCRIPTION (provided by applicant): Bronchopulmonary dysplasia (BPD) is a disease affecting infants who become oxygen dependent as a result of prolonged mechanical ventilation with supplemental oxygen early in life. Barotrauma and elevated levels of oxygen induce direct injury to the immature lung tissue, resulting in an inflammatory response and infiltration by circulating neutrophils. When neutrophils chemotax to the site of lung injury, the damage to the lung is compounded by the potent oxidant properties the neutrophils possess. Increased injury to the lung results in decreased blood oxygenation, requiring ventilation with progressively higher concentrations of oxygen that further accelerates the pace of injury. One way to break this vicious cycle of inflammation and injury is to block the recruitment of neutrophils to the lung. Novel inhibitors of neutrophil chemotaxis have been discovered that potently inhibit neutrophil chemotaxis both in vitro and in vivo. The goals of this SBIR Phase II proposal are to optimize the chemical structure of these chemotaxis inhibitors for potency, metabolic stability and intestinal absorption, and obtain the pharmacokinetic and toxicological data necessary for submission of an investigational new drug (IND) application for advancing these novel inhibitors towards clinical evaluation in humans.

描述（由申请人提供）：支气管肺发育异常（BPD）是一种影响婴儿的疾病，这些疾病因延长了生命早期的机械通气和补充氧的延长而依赖于氧气。低压和氧气升高会导致未成熟的肺组织直接损伤，从而导致炎症反应和循环中性粒细胞的浸润。当中性粒细胞趋化到肺损伤部位时，肺对肺的损害会因中性粒细胞所具有的有效氧化剂特性而加剧。增加对肺部的损伤导致血液氧合减少，需要逐渐加快氧气浓度升高，从而进一步加速损伤的速度。打破这种恶性炎症和伤害循环的一种方法是阻止中性粒细胞募集到肺部。已经发现，在体外和体内抑制中性粒细胞趋化性的新型抑制剂。该SBIR II期建议的目标是优化这些趋化性抑制剂的化学结构，以实现效力，代谢稳定性和肠道吸收，并获得用于提出研究新药（IND）应用这些新型抑制剂对人类临床评估的研究所必需的药代动力学和毒理学数据。