We describe the effects of pH on the structure and bioavailability of MIDD0301, an oral lead compound for asthma. MIDD0301 interacts with peripheral GABAA receptors to reduce lung inflammation and airway smooth muscle constriction. The structure of MIDD0301 combines basic imidazole and carboxylic acid function in the same diazepine scaffold, resulting in high solubility at neutral pH. Furthermore, we demonstrated that MIDD0301 can interconvert between a seven-membered ring structure at neutral pH and an acyclic compound at or below pH 3. Both structures have two stable conformers in solution that can be observed by 1H NMR at room temperature. Kinetic analysis showed opening and closing of the seven-membered ring of MIDD0301 at gastric and intestinal pH, occurring with different rate constants. However, in vivo studies showed that the interconversion kinetics are fast enough to yield similar MIDD0301 blood and lung concentrations for neutral and acidic formulations. Importantly, acidic and neutral formulations of MIDD0301 exhibit high lung distribution with low concentrations in brain. These findings demonstrate that MIDD0301 interconverts between stable structures at neutral and acidic pH without changes in bioavailability, further supporting its formulation as an oral asthma medication.

中文翻译：

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pH对咪唑基苯并二氮杂-3-羧酸盐MIDD0301的结构和生物利用度的影响。

我们描述了pH对MIDD0301（一种用于哮喘的口服先导化合物）的结构和生物利用度的影响。MIDD0301与周围的GABAA受体相互作用，以减少肺部炎症和气道平滑肌收缩。MIDD0301的结构在相同的二氮杂骨架中结合了碱性咪唑和羧酸的功能，从而在中性pH下具有高溶解度。此外，我们证明了MIDD0301可以在中性pH下的七元环结构与pH等于或低于pH 3的无环化合物之间相互转化。这两种结构在溶液中均具有两个稳定的构象异构体，可以在室温下通过1H NMR观察到。动力学分析表明MIDD0301的七元环在胃和肠的pH值下打开和关闭，其速率常数不同。然而，体内研究表明，对于中性和酸性制剂，相互转化动力学足够快，可以产生相似的MIDD0301血液和肺部浓度。重要的是，MIDD0301的酸性和中性配方在大脑中的肺分布较高，浓度较低。这些发现表明，MIDD0301在中性和酸性pH值之间在稳定结构之间相互转化，而没有生物利用度的变化，进一步支持了其作为口服哮喘药物的配方。