A medicinal chemists' guide to the unique difficulties of lead optimization for tuberculosis.
A medicinal chemists' guide to the unique difficulties of lead optimization for tuberculosis.
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DOI：
10.1016/j.bmcl.2013.07.006
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发表时间：
2013-09-01
影响因子：
2.7
通讯作者：
Barry, Clifton E., III
中科院分区：
文献类型：
--
作者：
Dartois, Veronique;Barry, Clifton E., III
结核病是一种细菌性疾病，主要影响肺部并导致广泛的组织病理学。这种病理学导致了药物开发的复杂性，因为它呈现出细菌驻留的离散微环境，通常在复制有限且内在药物敏感性较低的条件下。这种巩固的病理学还会导致血管化受损，从而限制潜在的先导分子进入感染部位。将这些考虑因素转化为目标产品概况以指导先导化合物优化计划涉及实施独特的体外和体内测定，以最大限度地提高开发具有临床意义的候选药物的可能性。
Tuberculosis is a bacterial disease which predominantly affects the lungs and results in extensive tissue pathology. This pathology contributes to the complexity of drug development as it presents discrete microenvironments within which the bacterium resides, often under conditions where replication is limited and intrinsic drug susceptibility is low. This consolidated pathology also results in impaired vascularization that limits access of potential lead molecules to the site of infection. Translating these considerations into a target-product profile to guide lead optimization programs involves implementing unique in vitro and in vivo assays to maximize the likelihood of developing clinically meaningful candidates.
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