Optimization of substituted imidazobenzodiazepines as novel asthma treatments.

ABSTRACT: We describe the synthesis of analogs of XHE-III-74, a selective α4β3γ2 GABA_AR ligand, shown to relax airway smooth muscle ex vivo and reduce airway hyperresponsiveness in a murine asthma model. To improve properties of this compound as an asthma therapeutic, a series of analogs with a deuterated methoxy group in place of methoxy group at C-8 position was evaluated for isotope effects in preclinical assays; including microsomal stability, cytotoxicity, and sensorimotor impairment. The deuterated compounds were equally or more metabolically stable than the corresponding non-deuterated analogs and increased sensorimotor impairment was observed for some deuterated compounds. Thioesters were more cytotoxic in comparison to other carboxylic acid derivatives of this compound series. Th

SUBMITTER: Jahan R 

PROVIDER: S-EPMC5253108 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature