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

描述（由申请人提供）：气道平滑肌（ASM）是严重哮喘的一个有吸引力的治疗靶点。目前的支气管扩张剂药物在严重哮喘中明显无效，可能是因为它们激活了一个漫长而复杂的松弛信号通路，其多个步骤容易受到炎症激活的通路的拮抗，这些通路混淆了松弛信号。相反，破坏ASM收缩的更有效策略是直接瞄准收缩器官。为此，我们在小鼠肺切片中发现了抑制平滑肌肌球蛋白聚合、放松人气道肌细胞和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方案，其中先导化合物在化学上的有效性，效力，选择性，安全性以及吸入时理想的药理学和药学特性进行了优化。该项目最终将开发一种新的候选药物，其临床前特性证明其适合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，该项目将导致一种新型哮喘药物（平滑肌肌球蛋白聚合抑制剂）的完整临床前开发，该药物具有全新的作用机制（实际上是溶解收缩装置），针对新的分子靶标（平滑肌肌球蛋白细丝）。因为它们能溶解肌凝蛋白细丝，我们把这种新型药物称为“肌溶蛋白”。

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)