Faculty Collaboration Database

A Novel Orally Available Asthma Drug Candidate That Reduces Smooth Muscle Constriction and Inflammation by Targeting GABA_A Receptors in the Lung. Mol Pharm 2018 May 07;15(5):1766-1777

Date

03/27/2018

Pubmed ID

29578347

Pubmed Central ID

PMC5954213

DOI

10.1021/acs.molpharmaceut.7b01013

Scopus ID

2-s2.0-85046694256 (requires institutional sign-in at Scopus site)   30 Citations

Abstract

We describe lead compound MIDD0301 for the oral treatment of asthma based on previously developed positive allosteric α₅β₃γ₂ selective GABA_A receptor (GABA_AR) 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 α_1-3,5β₃γ₂ GABA_ARs 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 GABA_AR ligands.

Author List

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

Authors

Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - Milwaukee
James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Animals
Asthma
Brain
Bronchoalveolar Lavage Fluid
CD4-Positive T-Lymphocytes
Constriction
Cytokines
Eosinophils
Female
Guinea Pigs
Inflammation
Ligands
Lung
Macrophages
Male
Mice
Mice, Inbred BALB C
Muscle, Smooth
Ovalbumin
Receptors, GABA-A
Respiratory Hypersensitivity