Preclinical development of myosolvins, a new class of medicine for asthma

肌溶解素（一种新型哮喘药物）的临床前开发

基本信息

批准号：
9334925
负责人：
DAVID L. MCCORMICK
金额：
--
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334925
关键词：
Acute Adrenal Cortex Hormones Adrenergic Agonists Adverse effects Aerosols Air Asthma Breathing Bronchoconstriction Bronchodilator Agents Canis familiaris Cavia Chemicals Chemistry Clinical Trials Complex Contracts Development Dose Drug Kinetics Elements Evaluation Excretory function Filament Formulation Funding Guidelines H19 gene Human In Vitro Inflammation Lead Lung Medicine Metabolism Microfilaments Minority Molecular Target Mus Muscle Muscle Cells Muscle Contraction Muscle relaxants Myosin ATPase National Heart, Lung, and Blood Institute Obstruction Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacy (field)Phase Process Program Development Property Public Health Rattus Research Risk Safety Signal Pathway Signal Transduction Slice Smooth Muscle Smooth Muscle Myosins Symptoms Testing Therapeutic Toxic effect Toxicology absorption airway muscle analog anti-IgE asthmatic base in vivo inhibitor/antagonist meetings novel novel drug class novel strategies novel therapeutics polymerization pre-clinical preclinical development preclinical evaluation prevent programs respiratory smooth muscle scale up small molecule therapeutic target

项目摘要

Description (provided by applicant): Airway smooth muscle (ASM) represents an attractive therapeutic target in severe asthma. Current bronchodilator medications are remarkably ineffective in severe asthma, probably because they activate a long and complex relaxant signaling pathway, whose multiple steps are vulnerable to antagonism by inflammation- activated pathways that confound relaxant signaling. Instead, a more robust strategy to disrupt ASM contraction is to target the contractile apparatus directly. To this end, we identified small molecules that inhibit smooth muscle myosin polymerization, relax human airway myocytes, and blunt bronchoconstriction in mouse lung slices and from these selected a lead compound. We now propose a comprehensive program in which the lead compound is chemically optimized for efficacy, potency, selectivity, safety, and desirable pharmacological and pharmaceutical properties when administered by inhalation. This program will culminate in the development of a new candidate medicine whose preclinical properties demonstrate its suitability for testing in human asthmatics. An IND application will be submitted to enable such testing. If successful, this project will result in the complete preclinical development of a new class of asthma medication (smooth muscle myosin polymerization inhibitor) with an entirely novel mechanism of action (literally dissolving the contractile apparatus) directed at a novel molecular target (smooth muscle myosin filaments). Because they dissolve myosin filaments, we call the new class of medication "myosolvins". (End of Abstract)

描述（由申请人提供）：气道平滑肌（ASM）代表严重哮喘中有吸引力的治疗靶标。当前的支气管扩张药在严重的哮喘中非常无效，可能是因为它们激活了长长而复杂的松弛信号传导途径，其多个步骤容易受到炎症激活的途径的拮抗，这会混淆松弛信号传导。相反，破坏ASM收缩的更强大的策略是直接针对收缩设备。为此，我们确定了抑制平滑肌肌球蛋白聚合，放松人气道肌细胞和钝的小支气管收缩的小分子，并从这些切片中选择了铅化合物。现在，我们提出了一项综合计划，其中通过吸入施用铅化合物，以实现功效，效力，选择性，安全性以及理想的药理和药理特性进行化学优化。该计划将最终导致开发一种新的候选医学，其临床前特性证明了其适合在人类哮喘患者中进行测试。 IND申请将提交以启用此类测试。如果成功的话，该项目将通过完全新颖的作用机理（从字面上溶解收缩的机制）（平滑的肌肉肌球蛋白丝）完全新颖，从而导致一种新的急诊哮喘药物（平滑肌肌球蛋白聚合抑制剂）的完整临床前开发。因为它们可以溶解肌球蛋白丝，所以我们称新的药物为“肌肉菌”。（抽象的结尾）