Anacor Pharmaceuticals , 1020 East Meadow Circle , Palo Alto , California 94303 , United States.
Centre for Drugs and Diagnostics, Department of Parasitology , Liverpool School of Tropical Medicine , Pembroke Place , Liverpool L3 5QA , U.K.
J Med Chem. 2019 Mar 14;62(5):2521-2540. doi: 10.1021/acs.jmedchem.8b01854. Epub 2019 Feb 26.
A series of pleuromutilins modified by introduction of a boron-containing heterocycle on C(14) of the polycyclic core are described. These analogs were found to be potent anti- Wolbachia antibiotics and, as such, may be useful in the treatment of filarial infections caused by Onchocerca volvulus, resulting in Onchocerciasis or river blindness, or Wuchereria bancrofti and Brugia malayi and related parasitic nematodes resulting in lymphatic filariasis. These two important neglected tropical diseases disproportionately impact patients in the developing world. The lead preclinical candidate compound containing 7-fluoro-6-oxybenzoxaborole (15, AN11251) was shown to have good in vitro anti- Wolbachia activity and physicochemical and pharmacokinetic properties providing high exposure in plasma. The lead was effective in reducing the Wolbachia load in filarial worms following oral administration to mice.
描述了一系列在多环核心的 C(14) 上引入含硼杂环的培罗霉素修饰物。这些类似物被发现是强效的抗沃尔巴克氏体抗生素，因此，可能有助于治疗由盘尾丝虫引起的丝虫感染，即盘尾丝虫病或河盲症，或由班氏吴策线虫和马来丝虫以及相关寄生线虫引起的淋巴丝虫病。这两种重要的被忽视热带病不成比例地影响着发展中国家的患者。含有 7-氟-6-氧代苯并恶硼烷（15，AN11251）的先导临床前候选化合物具有良好的体外抗沃尔巴克氏体活性以及理化和药代动力学特性，可在血浆中提供高暴露。该先导化合物在口服给予小鼠后，可有效降低丝虫蠕虫中的沃尔巴克氏体负荷。
