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

• 批准号: 8757703
• 负责人: DAVID L. MCCORMICK
• 金额: $ 176.14万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757703
• 关键词: Acute; Adrenal Cortex Hormones; Adrenergic Agonists; Adverse effects; Aerosols; Air; Asthma; Breathing; Bronchoconstriction; Bronchodilator Agents; Canis familiaris; Cavia; Chemistry; Clinical Trials; Complex; Contracts; Development; Dose; Drug Formulations; Drug Kinetics; Elements; Evaluation; Excretory function; Filament; 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; Pharmacy (field); Phase; Process; Property; Public Health; Rattus; Relative (related person); Research; Risk; Safety; Signal Pathway; Signal Transduction; Slice; Smooth Muscle; Smooth Muscle Myosins; Staging; Symptoms; Testing; Therapeutic; Toxic effect; Toxicology; absorption; abstracting; analog; anti-IgE; base; in vivo; inhibitor/antagonist; meetings; microbial alkaline proteinase inhibitor; novel; novel strategies; polymerization; pre-clinical; preclinical evaluation; prevent; programs; respiratory smooth muscle; scale up; small molecule; therapeutic target

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）代表了严重哮喘的一个有吸引力的治疗靶点。目前的支气管扩张药物对严重哮喘明显无效，可能是因为它们激活了一条长而复杂的松弛信号通路，该通路的多个步骤很容易受到炎症激活通路的拮抗，从而混淆松弛信号传导。相反，破坏 ASM 收缩的更稳健策略是直接针对收缩装置。为此，我们在小鼠肺切片中鉴定了抑制平滑肌肌球蛋白聚合、松弛人气道肌细胞以及钝化支气管收缩的小分子，并从中选择了一种先导化合物。我们现在提出了一个综合计划，其中先导化合物经过化学优化，以提高吸入给药时的功效、效力、选择性、安全性以及所需的药理学和药物特性。该计划最终将开发出一种新的候选药物，其临床前特性证明其适用于人类哮喘患者的测试。将提交 IND 申请以进行此类测试。如果成功，该项目将导致一类新型哮喘药物（平滑肌肌球蛋白聚合抑制剂）的完整临床前开发，该药物具有针对新分子靶点（平滑肌肌球蛋白丝）的全新作用机制（真正溶解收缩装置）。因为它们溶解肌球蛋白丝，我们将新型药物称为“肌溶解素”。 （摘要完）