Medicinal Chemistry, Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USA.
Future Med Chem. 2011 Oct;3(13):1585-605. doi: 10.4155/fmc.11.106.
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world today. Bronchodilators, particularly muscarinic antagonists and β(2) agonists, are recommended for patients with moderate to severe COPD. Dual-pharmacology muscarinic antagonist- β(2) agonist (MABA) molecules present an exciting new approach to the treatment of COPD by combining muscarinic antagonism and β(2) agonism in a single entity. They have the potential to demonstrate additive or synergistic bronchodilation over either pharmacology alone. Due to this enticing prospect, several companies have now reported MABA discovery efforts through a conjugated/linked strategy with one candidate (GSK-961081) demonstrating clinical proof of concept. Several MABA crystal forms have been identified, satisfying the requirements for inhaled dosing devices. There are significant challenges in designing MABAs, but the potential to achieve enhanced bronchoprotection in patients and facilitate 'triple therapy' makes this an extremely important and exciting area of pharmaceutical research.
慢性阻塞性肺疾病（COPD）是当今世界上主要的死亡原因之一。支气管扩张剂，特别是毒蕈碱拮抗剂和β（2）激动剂，被推荐用于中重度 COPD 患者。双药理学毒蕈碱拮抗剂-β（2）激动剂（MABA）分子为 COPD 的治疗提供了一种令人兴奋的新方法，即将毒蕈碱拮抗作用和β（2）激动作用结合在一个单一实体中。它们有可能在单独使用任何一种药物的基础上，表现出相加或协同的支气管扩张作用。由于这一诱人的前景，几家公司已经通过共轭/连接策略报告了 MABA 的发现工作，其中一个候选药物（GSK-961081）已经证明了临床概念验证。已经确定了几种 MABA 晶体形式，满足吸入给药装置的要求。设计 MABA 存在重大挑战，但在患者中实现增强的支气管保护作用并促进“三联疗法”的潜力，使其成为制药研究中一个极其重要和令人兴奋的领域。
