Biochemical and Structural Evaluation of Highly Selective 2-Arylbenzoxazole-Based Transthyretin Amyloidogenesis Inhibitors

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• 作者：Steven M. Johnson ; Stephen Connelly ; Ian A. Wilson ; Jeffery W. Kelly
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：January 24, 2008
• 年：2008
• 卷：51
• 期：2
• 页码：260 - 270
• 全文大小：1809K
• 年卷期：v.51,no.2(January 24, 2008)
• ISSN：1520-4804

文摘

To develop potent transthyretin (TTR) amyloidogenesis inhibitors that also display high binding selectivity in blood, it proves useful to systematically optimize each of the three substructural elements that comprise a typical inhibitor: the two aryl rings and the linker joining them. In the first study, described herein, structural modifications to one aryl ring were evaluated by screening a library of 2-arylbenzoxazoles bearing thyroid hormone-like aryl substituents on the 2-aryl ring. Several potent and highly selective amyloidogenesis inhibitors were identified that exhibit minimal thyroid hormone nuclear receptor and COX-1 binding. High resolution crystal structures (1.3–1.5 Å) of three inhibitors (2f, 4f, and 4d) in complex with TTR were obtained to characterize their binding orientation. Collectively, the results demonstrate that thyroid hormone-like substitution patterns on one aryl ring lead to potent and highly selective TTR amyloidogenesis inhibitors that lack undesirable thyroid hormone receptor or COX-1 binding.