Mizuguchi Mineyuki, Nakagawa Yusuke, Yokoyama Takeshi, Okada Takuya, Fujii Kanako, Takahashi Kanoko, Luan Nguyen Ngoc Thanh, Nabeshima Yuko, Kanamitsu Kayoko, Nakagawa Shinsaku, Yamakawa Shiori, Ueda Mitsuharu, Ando Yukio, Toyooka Naoki
Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan.
J Med Chem. 2024 Apr 26;67(9):6987-7005. doi: 10.1021/acs.jmedchem.3c02286.
Transthyretin amyloidosis is a fatal disorder caused by transthyretin amyloid aggregation. Stabilizing the native structure of transthyretin is an effective approach to inhibit amyloid aggregation. To develop kinetic stabilizers of transthyretin, it is crucial to explore compounds that selectively bind to transthyretin in plasma. Our recent findings demonstrated that the uricosuric agent benziodarone selectively binds to transthyretin in plasma. Here, we report the development of benziodarone analogues with enhanced potency for selective binding to transthyretin in plasma compared to benziodarone. These analogues featured substituents of chlorine, bromine, iodine, a methyl group, or a trifluoromethyl group, at the 4-position of the benzofuran ring. X-ray crystal structure analysis revealed that CH···O hydrogen bonds and a halogen bond are important for the binding of the compounds to the thyroxine-binding sites. The bioavailability of benziodarone analogues with 4-Br, 4-Cl, or 4-CH was comparable to that of tafamidis, a current therapeutic agent for transthyretin amyloidosis.
转甲状腺素蛋白淀粉样变性是一种由转甲状腺素蛋白淀粉样聚集引起的致命性疾病。稳定转甲状腺素蛋白的天然结构是抑制淀粉样聚集的有效方法。为了开发转甲状腺素蛋白的动力学稳定剂，探索能在血浆中选择性结合转甲状腺素蛋白的化合物至关重要。我们最近的研究结果表明，促尿酸排泄药苯碘达隆能在血浆中选择性结合转甲状腺素蛋白。在此，我们报告了苯碘达隆类似物的研发情况，与苯碘达隆相比，这些类似物在血浆中对转甲状腺素蛋白的选择性结合能力更强。这些类似物在苯并呋喃环的4位带有氯、溴、碘、甲基或三氟甲基取代基。X射线晶体结构分析表明，C-H···O氢键和卤键对于化合物与甲状腺素结合位点的结合很重要。带有4-溴、4-氯或4-甲基的苯碘达隆类似物的生物利用度与他氟米地相当，他氟米地是目前用于治疗转甲状腺素蛋白淀粉样变性的药物。
