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

Authors
  • Akama, Tsutomu1
  • Zhang, Yong-Kang1
  • Freund, Yvonne R1
  • Berry, Pamela1
  • Lee, Joanne1
  • Easom, Eric E1
  • Jacobs, Robert T1
  • Plattner, Jacob J1
  • Witty, Michael J2
  • Peter, Rosemary3
  • Rowan, Tim G3
  • Gillingwater, Kirsten4
  • Brun, Reto4
  • Nare, Bakela5
  • Mercer, Luke5
  • Xu, Musheng6
  • Wang, Jiangong6
  • Liang, Hao6
  • 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. , (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. , (China)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Jan 01, 2018
Volume
28
Issue
1
Pages
6–10
Identifiers
DOI: 10.1016/j.bmcl.2017.11.028
PMID: 29169674
Source
Medline
Keywords
License
Unknown

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.

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