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

  • Bioorg Med Chem Lett. 2018 Jan 1;28(1):6-10. doi: 10.1016/j.bmcl.2017.11.028.
Tsutomu Akama  1 ,  Yong-Kang Zhang  1 ,  Yvonne R Freund  1 ,  Pamela Berry  1 ,  Joanne Lee  1 ,  Eric E Easom  1 ,  Robert T Jacobs  1 ,  Jacob J Plattner  1 ,  Michael J Witty  2 ,  Rosemary Peter  3 ,  Tim G Rowan  3 ,  Kirsten Gillingwater  4 ,  Reto Brun  4 ,  Bakela Nare  5 ,  Luke Mercer  5 ,  Musheng Xu  6 ,  Jiangong Wang  6 ,  Hao Liang  6
Affiliations
  • 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. Electronic address: [email protected].
  • 3. Global Alliance for Livestock and Veterinary Medicine, Doherty Building, Pentlands Science Park, Penicuik, Edinburgh EH26 0PZ, UK.
  • 4. Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland; 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.
PMID: 29169674 DOI: 10.1016/j.bmcl.2017.11.028
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-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.

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