鉴定4-氟苄基L-缬氨酸酰胺苯并硼唑（AN11736）作为治疗动物非洲锥虫病（AAT）的潜在开发候选药物。
Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT).
作者信息
Akama Tsutomu, Zhang Yong-Kang, Freund Yvonne R, Berry Pamela, Lee Joanne, Easom Eric E, Jacobs Robert T, Plattner Jacob J, Witty Michael J, Peter Rosemary, Rowan Tim G, Gillingwater Kirsten, Brun Reto, Nare Bakela, Mercer Luke, Xu Musheng, Wang Jiangong, Liang Hao
机构信息
Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Global Alliance for Livestock and Veterinary Medicine, Doherty Building, Pentlands Science Park, Penicuik, Edinburgh EH26 0PZ, UK.
出版信息
Bioorg Med Chem Lett. 2018 Jan 1;28(1):6-10. doi: 10.1016/j.bmcl.2017.11.028. Epub 2017 Nov 20.
Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.
设计并合成了新型L-缬氨酸酰胺苯并硼氧六环及其类似物，用于结构活性关系（SAR）研究，以优化对刚果锥虫（T. congolense）和间日锥虫（T. vivax）寄生虫的生长抑制活性。该研究确定了4-氟苄基（1-羟基-7-甲基-1,3-二氢苯并[c][1,2]硼氧六环-6-羰基）-L-缬氨酸酯（5，AN11736），其对刚果锥虫的IC值为0.15 nM，对间日锥虫为1.3 nM，并且在感染小鼠模型（腹腔注射给药）和目标动物牛（肌肉注射给药）中，单剂量10 mg/kg对刚果锥虫和间日锥虫均显示出100%的疗效。AN11736已进入早期开发研究阶段。
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