A Novel Orally Available Asthma Drug Candidate That Reduces Smooth Muscle Constriction and Inflammation by Targeting GABA(A) Receptors in the Lung

作者：Forkuo Gloria S; Nieman Amanda N; Kodali Revathi; Zahn Nicolas M; Li Guanguan; Roni M S Rashid; Stephen Michael Rajesh; Harris Ted W; Jahan Rajwana; Guthrie Margaret L; Yu Olivia B; Fisher Janet L; Yocum Gene T; Emala Charles W; Steeber Douglas A; Stafford Douglas C; Cook James M; Arnold Leggy A

来源：Molecular Pharmaceutics, 2018, 15(5): 1766-1777.

DOI：10.1021/acs.molpharmaceut.7b01013

• asthma
• GABA(A) receptor
• airway hyperresponsiveness
• airway inflammation
• MIDD0301
• imidazobenzodiazepine

We describe lead compound MIDD0301 for the oral treatment of asthma based on previously developed positive allosteric alpha(5)beta(3)gamma(2) selective GABA(A) receptor (GABA(A)R) 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-alpha were reduced for MIDD0301-treated mice without changing antiinflammatory cytokine IL-10 levels. Automated patch clamp confirmed amplification of GABA induced current mediated by alpha(l-3,5)beta(3)gamma(2) GABA(A)Rs in the presence of MIDD0301. Pharmacodynamically, transmembrane currents of ex vivo CD4(+) T cells from asthmatic mice were potentiated Airway smooth 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 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.

• 出版日期2018-5