- Optimization of substituted imidazobenzodiazepines as novel asthma treatments
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We describe the synthesis of analogs of XHE-III-74, a selective α4β3γ2 GABAAR 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. The most promising compound 16 identified from the in vitro screens also strongly inhibited smooth muscle constriction in ex vivo guinea pig tracheal rings. Smooth muscle relaxation, determined by reduction of airway hyperresponsiveness with a murine ovalbumin sensitized and challenged model, showed that 16 was efficacious at low methacholine concentrations. However, this effect was limited due to suboptimal pharmacokinetics of 16. Based on these findings, further analogs of XHE-III-74 will be investigated to improve in vivo metabolic stability while retaining the efficacy at lung tissues involved in asthma pathology.
- Jahan, Rajwana,Stephen, Michael Rajesh,Forkuo, Gloria S.,Kodali, Revathi,Guthrie, Margaret L.,Nieman, Amanda N.,Yuan, Nina Y.,Zahn, Nicolas M.,Poe, Michael M.,Li, Guanguan,Yu, Olivia B.,Yocum, Gene T.,Emala, Charles W.,Stafford, Douglas C.,Cook, James M.,Arnold, Leggy A.
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- Studies in search of diazepam-insensitive subtype selective agents for GABA/Bz receptors
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In search of more selective ligands for "diazepam-insensitive" (DI) GABA receptors (i.e. receptors containing either an α4 or α6 subunit), a series of 3- and 8-substituted 6-oxo-imidazo [1,5a] [1,4]-benzodiazepines were synthesized and evaluated in vitro on recombinant human GABAA (receptor) subtypes to study their structure activity relationships. In agreement with previous findings,1,2 it was found the size of ring-D exerted a marked influence on the binding affinity at all receptor subtypes. Based on this finding, the most DI selective ligands in vitro [CM-D45 (10) and XHeIII-74 (37)] have been synthesized.
- Li, Xiaoyan,Ma, Chunrong,He, Xiaohui,Yu, Jianming,Han, Dongmei,Zhang, Chunchun,Atack, John R.,Cook, James M.
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p. 504 - 537
(2007/10/03)
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