Structure-Activity Relationships for Amide-, Carbamate-, And Urea-Linked Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)
Structure-Activity Relationships for Amide-, Carbamate-, And Urea-Linked Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)
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DOI：
10.1021/jm2012276
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发表时间：
2012-01-12
影响因子：
7.3
通讯作者：
Denny, William A.
中科院分区：
文献类型：
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作者：
Blaser, Adrian;Palmer, Brian D.;Denny, William A.
研究了临床结核药物(6S)-2-硝基-6-{[4-（三氟甲氧基）苄基]氧}-6,7-二氢- 5h -咪唑[2,1-b][1,3]恶嗪（PA-824）的类似物，其中OCH2键被酰胺、氨基甲酸酯和尿素取代，作为解决氧化代谢、降低亲脂性和改善水溶性的替代方法。一些可溶性单芳基样品显示出适度改善（类似于2至4倍）对复制结核分枝杆菌的效力，但在厌氧（非复制）条件下通常是较差的抑制剂。亲脂性更强的联芳基衍生物大多表现出与亲本联芳基系列相似或降低的效力。在急性结核分枝杆菌感染小鼠模型中，主要的氨基甲酸联芳酯表现出特殊的代谢稳定性和比母体药物好5倍的疗效，但难溶性。用芳基哌嗪替代联芳基部分产生了一种可溶的、口服生物可利用的氨基甲酸酯类似物，在急性模型中具有相同的活性，在慢性感染模型中具有与OPC-67683相当的疗效，在几种物种中具有良好的药代动力学特征，并且增强了安全性。
Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH2 linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (similar to 2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.