A Novel Orally Available Asthma Drug Candidate That Reduces Smooth Muscle Constriction and Inflammation by Targeting GABA(A) Receptors in the Lung.
A Novel Orally Available Asthma Drug Candidate That Reduces Smooth Muscle Constriction and Inflammation by Targeting GABA(A) Receptors in the Lung.
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DOI：
10.1021/acs.molpharmaceut.7b01013
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发表时间：
2018-05-07
影响因子：
4.9
通讯作者：
Arnold LA
中科院分区：
文献类型：
--
作者：
Forkuo GS;Nieman AN;Kodali R;Zahn NM;Li G;Rashid Roni MS;Stephen MR;Harris TW;Jahan R;Guthrie ML;Yu OB;Fisher JL;Yocum GT;Emala CW;Steeber DA;Stafford DC;Cook JM;Arnold LA
我们描述了口服治疗哮喘的先导化合物MIDD0301，基于先前开发的正变构α5β3γ2选择性GABA受体(GABA AR)配体。MIDD0301在单个微摩尔浓度下松弛气道平滑肌，如体外豚鼠气管环所示。MIDD0301还通过口服给药减轻了卵蛋白哮喘小鼠模型的气道高反应性(AHR)。小鼠支气管肺泡灌洗液中嗜酸性粒细胞和巨噬细胞数量减少，但未见粘液化生。重要的是，经MIDD0301处理的小鼠肺组织细胞因子IL-17A、IL-4和肿瘤坏死因子-α的表达减少，而抗炎细胞因子IL-10水平没有改变。全自动膜片钳证实α1-3，5β3γ2 GABAARs在MIDD0301存在的情况下可介导GABA诱导电流的放大。药效学研究表明，在GABA存在下，MIDD0301可增强哮喘小鼠外周血中CD4+T细胞的跨膜电流。口服MIDD0301 20 mg/kg，可使小鼠肺组织中的CD_4~+T细胞减少。为期5天。药代动力学研究(PK)表明，在使用旋转棒进行感觉运动研究时，治疗小鼠的半衰期几乎为14小时，没有对中枢神经系统的不良影响。PK研究也证实了非常低的大脑分布。总之，MIDD0301代表了一种安全和改进的口服哮喘药物候选药物，它可以松弛呼吸道平滑肌，减轻肺部炎症，从而以低于先前报道的GABAAR配体的剂量减少AHR。
We describe lead compound MIDD0301 for the oral treatment of asthma based on previously developed positive allosteric α5β3γ2 selective GABAA receptor (GABAAR) 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 broncho-alveolar 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 anti-inflammatory cytokine IL-10 levels. Automated patch clamp confirmed amplification of GABA induced current mediated by α1-3,5β3γ2 GABAARs 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 cell 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 hours 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 GABAAR ligands.
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影响因子：
4.9
作者：
Forkuo GS;Guthrie ML;Yuan NY;Nieman AN;Kodali R;Jahan R;Stephen MR;Yocum GT;Treven M;Poe MM;Li G;Yu OB;Hartzler BD;Zahn NM;Ernst M;Emala CW;Stafford DC;Cook JM;Arnold LA
通讯作者：
Arnold LA
影响因子：
4.9
作者：
Forkuo GS;Nieman AN;Yuan NY;Kodali R;Yu OB;Zahn NM;Jahan R;Li G;Stephen MR;Guthrie ML;Poe MM;Hartzler BD;Harris TW;Yocum GT;Emala CW;Steeber DA;Stafford DC;Cook JM;Arnold LA
通讯作者：
Arnold LA
DOI：
10.1152/ajplung.00107.2014
发表时间：
2015-05-01
影响因子：
4.9
作者：
Gallos, George;Yocum, Gene T.;Emala, Charles W., Sr.
通讯作者：
Emala, Charles W., Sr.
影响因子：
5.5
作者：
HALL, JM;MORTON, IKM
通讯作者：
MORTON, IKM
影响因子：
14.2
作者：
Israel, E;Chervinsky, PS;Edelman, JM
通讯作者：
Edelman, JM