Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT) |
| |
| Authors: | Tsutomu Akama Yong-Kang Zhang Yvonne R Freund Pamela Berry Joanne Lee Eric E Easom Robert T Jacobs Jacob J Plattner Michael J Witty Rosemary Peter Tim G Rowan Kirsten Gillingwater Reto Brun Bakela Nare Luke Mercer Musheng Xu Jiangong Wang Hao Liang |
| |
| Institution: | 1. Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA;2. Global Alliance for Livestock and Veterinary Medicine, Doherty Building, Pentlands Science Park, Penicuik, Edinburgh EH26 0PZ, UK;3. Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland;4. University of Basel, Petersplatz 1, 4003 Basel, Switzerland;5. Avista Pharma Solutions, 350 Tricenter Boulevard, Suite C, Durham, NC 27713, USA;6. Wuxi AppTec (Tianjin) Co. Ltd., No. 168 NanHai Road, 10th Avenue, TEDA, Tianjin 300457, PR China |
| |
| Abstract: | 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-dihydrobenzoc]1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 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. |
| |
| Keywords: | Benzoxaborole Trypanosomiasis Cattle SAR Lead optimisation Protozoan |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
