Identification of a 4-fluorobenzyl L-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)

被引：33

作者：

Akama, Tsutomu ^{[1
]}

Zhang, Yong-Kang ^{[1
]}

Freund, Yvonne R. ^{[1
]}

Berry, Pamela ^{[1
]}

Lee, Joanne ^{[1
]}

Easom, Eric E. ^{[1
]}

Jacobs, Robert T. ^{[1
]}

Plattner, Jacob J. ^{[1
]}

Witty, Michael J. ^{[2
]}

Peter, Rosemary ^{[2
]}

Rowan, Tim G. ^{[2
]}

Gillingwater, Kirsten ^{[3
,4
]}

Brun, Reto ^{[3
,4
]}

Nare, Bakela ^{[5
]}

Mercer, Luke ^{[5
]}

Xu, Musheng ^{[6
]}

Wang, Jiangong ^{[6
]}

Liang, Hao ^{[6
]}

机构：

[1] Anacor Pharmaceut Inc, 1020 E Meadow Circle, Palo Alto, CA 94303 USA

[2] Global Alliance Livestock & Vet Med, Doherty Bldg,Pentlands Sci Pk, Edinburgh EH26 0PZ, Midlothian, Scotland

[3] Swiss Trop & Publ Hlth Inst, Socinstr 57, CH-4051 Basel, Switzerland

[4] Univ Basel, Peterspl 1, CH-4003 Basel, Switzerland

[5] Avista Pharma Solut, 350 Trictr Blvd,Suite C, Durham, NC 27713 USA

[6] Wuxi AppTec Tianjin Co Ltd, TEDA, 168 NanHai Rd,10th Ave, Tianjin 300457, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 01期

基金：

比尔及梅琳达.盖茨基金会;

关键词：

Benzoxaborole; Trypanosomiasis; Cattle; SAR; Lead optimisation; Protozoan;

D O I：

10.1016/j.bmcl.2017.11.028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 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. (C) 2017 The Authors. Published by Elsevier Ltd.

引用

页码：6 / 10

页数：5

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