Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
Medicinal Chemistry Department, Charles River Laboratories, Chesterford Research Park, Saffron Walden, CB10 1XL, Cambridgeshire, United Kingdom.
Bioorg Med Chem Lett. 2021 Jun 1;41:127975. doi: 10.1016/j.bmcl.2021.127975. Epub 2021 Mar 19.
The targeting of both the muscarinic and β-adrenergic pathways is a well validated therapeutic approach for the treatment of chronic obstructive pulmonary disease (COPD). In this communication we report our effort to incorporate two pharmacologies into a single chemical entity, whose characteristic must be suitable for a once daily inhaled administration. Contextually, we aimed at a locally acting therapy with limited systemic absorption to minimize side effects. Our lung-tailored design of bifunctional compounds that combine the muscarinic and β-adrenergic pharmacologies by the elaboration of the muscarinic inhibitor 7, successfully led to the potent, pharmacologically balanced muscarinic antagonist and β agonist (MABA) 13.
同时针对毒蕈碱和β-肾上腺素能途径是一种经过充分验证的治疗慢性阻塞性肺疾病（COPD）的方法。在本通讯中，我们报告了将两种药理学结合到单一化学实体中的努力，其特征必须适合每日一次吸入给药。相应地，我们旨在实现局部作用的治疗方法，以限制全身吸收，从而最大程度地减少副作用。我们通过精心设计的双功能化合物来实现毒蕈碱和β-肾上腺素能药理学的结合，这些化合物将毒蕈碱抑制剂 7 进行了修饰，成功地得到了强效、药理学平衡的毒蕈碱拮抗剂和β激动剂（MABA）13。
