Optimization of substituted imidazobenzodiazepines as novel asthma treatments

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• 作者：Rajwana Jahan^a ; ¹ ; Michael Rajesh Stephen^a ; ¹ ; Gloria S. Forkuo^a ; Revathi Kodali^a ; Margaret L. Guthrie^a ; Amanda N. Nieman^a ; Nina Y. Yuan^a ; Nicolas M. Zahn^a ; Michael M. Poe^a ; Guanguan Li^a ; Olivia B. Yu^a ; Gene T. Yocum^b ; Charles W. Emala^b ; Douglas C. Stafford^a ; James M. Cook^a ; ^{capncook@uwm.edu} ; Leggy A. Arnold^a ; ^{arnold2@uwm.edu}
• 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.