Optimization of substituted imidazobenzodiazepines as novel asthma treatments

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• 作者：Rajwana Jahanp>ap>p> ; p>p>1p> ; Michael Rajesh Stephenp>ap>p> ; p>p>1p> ; Gloria S. Forkuop>ap> ; Revathi Kodalip>ap> ; Margaret L. Guthriep>ap> ; Amanda N. Niemanp>ap> ; Nina Y. Yuanp>ap> ; Nicolas M. Zahnp>ap> ; Michael M. Poep>ap> ; Guanguan Lip>ap> ; Olivia B. Yup>ap> ; Gene T. Yocump>bp> ; Charles W. Emalap>bp> ; Douglas C. Staffordp>ap> ; James M. Cookp>ap>p> ; p>p>capncook@uwm.edup> ; Leggy A. Arnoldp>ap>p> ; p>p>arnold2@uwm.edup>
• 关键词：XHE-III-74 ; Deuterated compounds ; Asthma ; GABAA receptor ; Airway hyperresponsiveness ; Airway smooth muscle
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：27 January 2017
• 年：2017
• 卷：126
• 期：Complete
• 页码：550-560
• 全文大小：1727 K
• 卷排序：126

文摘

Deuterated and non-deuterated compounds were compared using preclinical assays. Microsomal stability assays can be used to exclude drug candidates but fall short in selection of compounds stable in vivo. A novel analog of XHE-III-74, compound 16, was identified as a potent inhibitor of airway smooth muscle contraction ex vivo. Reduction of airway hyperresponsiveness by 16 in a murine model of asthma was observed despite suboptimal pharmacokinetics.