Modified Carbohydrate Scaffolds for the Treatment of Mucus Disease of the Airway

用于治疗气道粘液疾病的改良碳水化合物支架

基本信息

批准号：
9338292
负责人：
Stefan Oscarson
金额：
$ 28.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9338292
关键词：
Acetylcysteine Address Adrenal Cortex Hormones Adrenergic beta-Agonists Aerosols Agonist Albuterol Amino Acids Anti-Cholinergics Asthma Budesonide Carbohydrate Chemistry Carbohydrates Characteristics Chronic Obstructive Airway Disease Cleaved cell Collaborations Cysteine Cystic Fibrosis Data Dependence Disease Disulfide Linkage Disulfides Drug Kinetics Epithelial Cells Excipients Formulation Galactosides Gel Goals Human In Vitro Infection Inhalators Ipratropium Bromide Label Lead Libraries Lung Lung diseases Mucins Mucolytics Mucous body substance Mus Muscarinic Antagonists Nature Nebulizer Oxidation-Reduction Oxidative Stress Pathologic Pathology Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacy (field)Powder dose form Process Program Development Property Reaction Reagent Reducing Agents Safety Smell Perception Structure-Activity Relationship Sulfhydryl Compounds Symptoms Testing Therapeutic Toxic effect Variant Work airway obstruction analog base clinical candidate college cost crosslink crystallinity data integration design disulfide bond drug development formoterol hydroxyl group in vivo novel novel drug class oxidation particle practical application pre-clinical programs recombinant human DNase scaffold solid state

项目摘要

Project Summary Available therapeutics for treatment of pathologic mucus in airway diseases such as cystic fibrosis (CF), asthma, and COPD are limited in number, efficacy, and tolerability. Because excessive numbers of mucin disulfide bonds stiffen the airway mucus gel in CF, we have synthesized thiol-modified saccharides (“thiol- saccharides”) as a novel drug class that cleaves disulfide bridges to have excellent mucolytic activity. The rationale behind choosing a carbohydrate scaffold is that they are polar, cheap, “natural”, often crystalline, and, with their abundance of hydroxyl groups as well as chiral centers, offer easy access to analogues for structure activity relationship (SAR) studies. Preliminary data show that selected thiol-saccharides in our library have a faster onset of action and better potency than thiol amino acid compounds such as N-acetyl cysteine. Our preliminary data also provide reassurance about the safety of thiol-saccharides in vitro (airway epithelial cells) and in vivo (mouse lungs). We therefore propose two Aims to advance a drug development program for thiol- saccharides as a novel mucolytic treatment for mucus pathology in cystic fibrosis and other mucus associated lung diseases. In Aim 1 we will design and synthesize a library of thiol-saccharides to investigate and establish SARs for their mucolytic effect (in collaboration with Project 2) as well as their toxicity and other pharmacokinetic properties (in collaboration with Project 3). In Aim 2 we will evaluate the synthetic thiolsaccharides for their physicochemical properties, aerosolization characteristics, and stability as spray dried compounds with the goal to optimize formulation as excipient-free/excipient-minimized, high active loaded microparticles with suitable physicochemical and aerodynamic properties for pulmonary delivery via dry powder inhaler. Aim 2 will also co-formulate thiol-saccharides with other active pharmaceutical ingredients such as beta agonists, anticholinergics, corticosteroids, and rhDNAse.

项目摘要可用的治疗病理性粘液在气道疾病中的治疗疗法，例如囊性纤维化（CF），哮喘和COPD的数量，效率和耐受性受到限制。因为多余的粘蛋白二硫键使气道粘液凝胶在CF中加强，我们已经合成了硫醇改性的糖（“硫醇 - 糖”）作为一种新型的药物类别，它裂解二硫键具有出色的粘液溶剂活性。选择碳水化合物支架的基本原理是它们是极性的，便宜的，自然的，通常是结晶的，并且凭借丰富的羟基和手性中心，可轻松地访问结构的类似物活动关系（SAR）研究。初步数据表明，我们库中选定的硫代糖具有比硫醇氨基酸化合物（如N-乙酰基半胱氨酸）更快地发作和更好的效力。我们的初步数据还提供了关于硫代糖在体外安全性（气道上皮细胞）的安全性的保证和体内（小鼠肺）。因此，我们提出了两个目标，以推进针对硫醇的药物开发计划糖水作为囊性纤维化和其他粘液相关的粘液病理学的新型粘液溶剂治疗肺部疾病。在AIM 1中，我们将设计和合成一个硫代糖库来调查和建立 SARS粘液溶液效应（与项目2合作）以及其毒性和其他药代动力学特性（与项目3合作）。在AIM 2中，我们将评估合成喷雾干燥时，其物理特性，雾化特性和稳定性旨在优化公式为无赋形剂/偏用最小的，高活性的化合物微粒具有合适的物理和空气动力特性，可通过干燥粉吸入器。 AIM 2还将与其他活性药物成分合成硫醇 - 糖。例如β激动剂，抗胆碱能，皮质类固醇和Rhdnase。