Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery , University of Wisconsin-Milwaukee , Milwaukee , Wisconsin 53211 , United States.
Department of Pharmacology, Physiology & Neuroscience , University of South Carolina School of Medicine , Columbia , South Carolina 29208 , United States.
Mol Pharm. 2018 May 7;15(5):1766-1777. doi: 10.1021/acs.molpharmaceut.7b01013. Epub 2018 Apr 2.
We describe lead compound MIDD0301 for the oral treatment of asthma based on previously developed positive allosteric αβγ selective GABA receptor (GABAR) ligands. MIDD0301 relaxed airway smooth muscle at single micromolar concentrations as demonstrated with ex vivo guinea pig tracheal rings. MIDD0301 also attenuated airway hyperresponsiveness (AHR) in an ovalbumin murine model of asthma by oral administration. Reduced numbers of eosinophils and macrophages were observed in mouse bronchoalveolar lavage fluid without changing mucous metaplasia. Importantly, lung cytokine expression of IL-17A, IL-4, and TNF-α were reduced for MIDD0301-treated mice without changing antiinflammatory cytokine IL-10 levels. Automated patch clamp confirmed amplification of GABA induced current mediated by αβγ GABARs in the presence of MIDD0301. Pharmacodynamically, transmembrane currents of ex vivo CD4 T cells from asthmatic mice were potentiated by MIDD0301 in the presence of GABA. The number of CD4 T cells observed in the lung of MIDD0301-treated mice were reduced by an oral treatment of 20 mg/kg b.i.d. for 5 days. A half-life of almost 14 h was demonstrated by pharmacokinetic studies (PK) with no adverse CNS effects when treated mice were subjected to sensorimotor studies using the rotarod. PK studies also confirmed very low brain distribution. In conclusion, MIDD0301 represents a safe and improved oral asthma drug candidate that relaxes airway smooth muscle and attenuates inflammation in the lung leading to a reduction of AHR at a dosage lower than earlier reported GABAR ligands.
我们描述了一种基于先前开发的正变构 αβγ 选择性 GABA 受体（GABAR）配体的用于治疗哮喘的先导化合物 MIDD0301。MIDD0301 在离体豚鼠气管环中以单微摩尔浓度松弛气道平滑肌。MIDD0301 还通过口服给药减弱了卵清蛋白哮喘小鼠模型中的气道高反应性（AHR）。在没有改变粘液化生的情况下，在小鼠支气管肺泡灌洗液中观察到嗜酸性粒细胞和巨噬细胞数量减少。重要的是，MIDD0301 治疗的小鼠肺细胞因子表达的白细胞介素 17A、白细胞介素 4 和肿瘤坏死因子-α 减少，而抗炎细胞因子白细胞介素 10 水平没有改变。自动膜片钳证实 MIDD0301 存在时，增强了 GABA 诱导的αβγ GABAR 介导的电流。在存在 GABA 的情况下，MIDD0301 增强了来自哮喘小鼠的离体 CD4 T 细胞的跨膜电流。MIDD0301 治疗的小鼠肺中观察到的 CD4 T 细胞数量减少了 20 mg/kg b.i.d. 连续 5 天口服治疗。药代动力学（PK）研究表明半衰期接近 14 h，用旋转棒进行感觉运动研究时未观察到治疗小鼠有中枢神经系统不良反应。PK 研究还证实了脑分布非常低。总之，MIDD0301 代表了一种安全且改善的口服哮喘候选药物，可松弛气道平滑肌并减轻肺部炎症，从而在低于先前报道的 GABAR 配体的剂量下降低 AHR。
