A novel synthetic strategy was employed to synthesize compounds structurally related to asthma drug candidate MIDD0301. Following the generation of the desired imidazobenzodiazepines, the aqueous solubility was determined using the shake flask method and the apparent permeability was tested using a parallel artificial membrane permeability assay (PAMPA). The results of these assays showed moderate to high solubility and low permeability of the tested compounds. Compounds were then screened for toxicity using a Cell-Titer Glo assay, followed by an in-vivo open field study to identify potential adverse CNS effects. All tested compounds were non-toxic at concentrations up to 300 µM, and cause no behavioral changes in mice. The ability for the novel analogs to bind to GABAARs was determined and the results were compared to computational binding scores obtained from docking using Molecular Operating Environment (MOE). The substitution pattern of the novel analogs proved to play a great tole in their ability to bind to GABAARs resulting in an excellent structure-activity relationship. Finally, the ability for the compounds to reduce the asthmatic phenotype in mice was determined by double chamber non-invasive airway mechanics. A relationship between the reduction of airway hyperresponsiveness and GABAAR binding was observed. A similar structure-activity relationship was observed for airway smooth muscle relaxation using ex vivo Guinea pig tracheal rings in response substance P

Synthesis, biological evaluation, and molecular modeling of novel imidazobenzodiazepines to identify lead compounds for the oral treatment of asthma

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