Development of novel pegylated imidazobenzodiazepines as inhaled asthma drug candidates.

In this work, we identified a novel asthma drug candidate that upon nebulized administration reduced airway hyperresponsiveness in A/J mice comparable to the beta agonist albuterol. We identified this compound among synthesized pegylated imidazodiazepines with substituent variations in two positions. These compounds combine good affinity towards the gamma aminobutyric acid (A) receptors (GABAARs) expressed in the lungs and a polyethylene glycol (PEG) chain for excellent aqueous solubility to allow nebulization. As expected, the aqueous solubility of these derivatives increased with the PEG chain length and plateaued for compounds with four PEG units. The affinity towards GABAAR was influenced by the length of the PEG substituent. The most promising pegylated GABAAR ligand relaxed substance P constricted Guinea pig trachea rings and potentiated the effect of the beta agonist isoproterenol in acetylcholine constricted mouse trachea. Pharmacokinetic studies identified lung concentrations of compound 15 that were high enough to activate GABA(A) receptors in the lung. We also identified a metabolite of compound 15 in the lung that was subsequently synthesized. The metabolite 29 potentiated the activity of bronchodilator isoproterenol and reduced airway hyperresponsiveness in vivo.