Tissue-selective GABA(A) receptor modulators for asthma and bronchoconstrictive airway disease

This technology is a class of imidazobenzodiazepine compounds that can treat asthma and other bronchoconstrictive diseases while avoiding the centrally-mediated sedative effects of conventional benzodiazepines.

Unmet Need: Non-sedating bronchodilators that curb airway inflammation

Asthma and related bronchoconstrictive diseases such as chronic obstructive pulmonary disease affect hundreds of millions of people, yet the only drug classes available to reverse acute airway smooth muscle constriction remain β-adrenoceptor agonists and anticholinergics. These agents can lose effectiveness with chronic use and do not address the underlying airway inflammation, while add-on biologics and oral corticosteroids carry high costs or systemic side effects. A therapy that relaxes airway smooth muscle through an independent mechanism and simultaneously reduces inflammation would benefit the large population of patients whose disease is inadequately controlled by current options.

The Technology: Airway-selective GABA(A) modulators that avoid CNS sedation

This technology selectively controls smooth muscle contraction and inflammation as a method to treat asthma and other bronchoconstrictive airway diseases. By using imidazobenzodiazepine compounds that are specific to a subtype of GABA(A) receptors predominantly expressed on airway smooth muscle cells, this technology can potentiate GABA-induced relaxation of contracted airway smooth muscle to treat inflammation. Chemical modifications limit blood-brain barrier penetration, so the compounds act on peripheral airway receptors while minimizing associated CNS sedation. In preclinical studies, this technology has been shown to reduce airway hyperresponsiveness and lung inflammation in a mouse model of asthma.

Applications:

• Treatment of asthma, including acute bronchoconstriction and airway hyperresponsiveness
• Treatment of other bronchoconstrictive diseases such as chronic obstructive pulmonary disease (COPD) and bronchopulmonary dysplasia
• Reduction of airway inflammation in allergic and eosinophilic airway disease
• Inhaled or oral bronchodilator therapy that avoids central nervous system sedation
• Adjunct to existing controller therapies (e.g., inhaled corticosteroids) for inadequately controlled disease

Advantages:

• Relaxes airway smooth muscle through a mechanism independent of β-adrenoceptors and anticholinergic pathways
• Combines bronchodilation with anti-inflammatory activity in a single agent
• Tissue-specific targeting of GABA(A) receptors
• Limited blood-brain barrier penetration
• Avoids the sedation of conventional benzodiazepines
• Amenable to both inhaled and oral delivery

Lead Inventor:

Charles W. Emala Sr, M.D.

Patent Information:

Patent Pending (US20260125388)

Related Publications:

• Kowalczyk ET, Medubi KM, Meyer MJ, Toriola MA, Haasch TJ, Vesperman MR, Webb DA, Stafford DC, Yocum GT, Emala CW, Arnold LA.Development of novel pegylated imidazobenzodiazepines as inhaled asthma drug candidates.”Respir Med. 2025 Nov -Dec;249:108449.

• Webb DA, Meyer MJ, Medubi KM, Tylek AS, Yocum GT, Roni MSR, Zahn NM, Swartwout SA, Masoud AK, Emala CW, Stafford DC, Arnold LA. “Design, Synthesis, and Biological Evaluation of Novel Spiro Imidazobenzodiazepines to Identify Improved Inhaled Bronchodilators.” J Med Chem. 2023 Jul 27;66(14):9853-9865.

• Perez-Zoghbi JF, Sajorda DR, Webb DA, Arnold LA, Emala CW, Yocum GT. Imidazobenzodiazepine PI320 Relaxes Mouse Peripheral Airways by Inhibiting Calcium Mobilization. Am J Respir Cell Mol Biol. 2022 Oct;67(4):482-490.

• Rashid Roni MS, Zahn NM, Yocum GT, Webb DA, Mian MY, Meyer MJ, Tylek AS, Cook JM, Emala CW, Stafford DC, Arnold LA. “Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer.” Drug Dev Res. 2022 Jun;83(4):979-992.

• Zahn NM, Roni MSR, Yocum GT, Meyer MJ, Webb DA, Mian MY, Cook JM, Stafford DC, Emala CW, Arnold LA. “Development of Inhaled GABA(A) Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders.” ACS Pharmacol Transl Sci. 2022 Feb 1;5(2):8088.

• Zahn NM, Mikulsky BN, Roni MSR, Yocum GT, Mian MY, Knutson DE, Cook JM, Emala CW, Stafford DC, Arnold LA. “Nebulized MIDD0301 Reduces Airway Hyperresponsiveness in Moderate and Severe Murine Asthma Models.” ACS Pharmacol Transl Sci. 2020 Dec 2;3(6):1381-1390.

• Yocum GT, Perez-Zoghbi JF, Danielsson J, Kuforiji AS, Zhang Y, Li G, Rashid Roni MS, Kodali R, Stafford DC, Arnold LA, Cook JM, Emala CW Sr. “A novel GABAA receptor ligand MIDD0301 with limited blood-brain barrier penetration relaxes airway smooth muscle ex vivo and in vivo.” Am J Physiol Lung Cell Mol Physiol. 2019 Feb 1; 316(2): L385–L390.

Tech Ventures Reference:

• IR CU18058, CU24261

• Licensing Contact: Maria Rahmany