Abstract：
Clinical guidelines for COPD and asthma recommend inhaled β-adrenergic agonists, muscarinic antagonists, and, for frequent exacerbators, inhaled corticosteroids, with the challenge of combining them into a single device. The MABA (muscarinic antagonist and β2 agonist) concept has the potential to simplify this complexity while increasing the efficacy of both pharmacologies. In this article, we report the outcome of our solid-state driven back-up program that led to the discovery of the MABA compound CHF-6550. A soft drug approach was applied, aiming at high plasma protein binding and high hepatic clearance, concurrently with an early stage assessment of crystallinity through a dedicated experimental workflow. A new chemotype was identified, the diphenyl hydroxyacetic esters, able to generate crystalline material. Among this class, CHF-6550 demonstrated in vivo efficacy, suitability for dry powder inhaler development, favorable pharmacokinetics, and safety in preclinical settings and was selected as a back-up candidate, fulfilling the desired pharmacological and solid-state profile.
摘要：
COPD和哮喘的临床指南推荐吸入性β-肾上腺素能激动剂，毒蕈碱拮抗剂，and,对于经常飞行的飞行器来说，吸入皮质类固醇,面临着将它们组合到一个单一设备中的挑战。MABA(毒蕈碱拮抗剂和β2激动剂)概念具有简化这种复杂性的潜力,同时增加两种药理学的功效。在这篇文章中,我们报告了导致发现MABA化合物CHF-6550的固态驱动备份程序的结果。应用了一种软药物方法，针对高血浆蛋白结合和高肝脏清除率，同时通过专门的实验工作流程对结晶度进行早期评估。鉴定出一种新的化学型,二苯基羟基乙酸酯，能够产生晶体材料。在这个班里,CHF-6550表现出体内功效，适用于干粉吸入器的开发，有利的药代动力学，以及临床前环境中的安全性，并被选为后备候选人，履行所需的药理学和固态概况。
