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

Akama T; Zhang YK; Freund YR; Berry P; Lee J; Easom EE; Jacobs RT; Plattner JJ; Witty MJ; Peter R; Rowan TG; Gillingwater K; Brun R; Nare B; Mercer L; Xu M; Wang J; Liang H

doi:10.1016/j.bmcl.2017.11.028

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Journal article

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

Akama T Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Zhang YK Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Freund YR Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Berry P Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Lee J Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Easom EE Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Jacobs RT Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Plattner JJ Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Witty MJ Global Alliance for Livestock and Veterinary Medicine, Doherty Building, Pentlands Science Park, Penicuik, Edinburgh EH26 0PZ, UK. Electronic address: michael.witty@galvmed.org.
Peter R Global Alliance for Livestock and Veterinary Medicine, Doherty Building, Pentlands Science Park, Penicuik, Edinburgh EH26 0PZ, UK.
Rowan TG Global Alliance for Livestock and Veterinary Medicine, Doherty Building, Pentlands Science Park, Penicuik, Edinburgh EH26 0PZ, UK.
Gillingwater K Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland; University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
Brun R Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland; University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
Nare B Avista Pharma Solutions, 350 Tricenter Boulevard, Suite C, Durham, NC 27713, USA.
Mercer L Avista Pharma Solutions, 350 Tricenter Boulevard, Suite C, Durham, NC 27713, USA.
Xu M Wuxi AppTec (Tianjin) Co. Ltd., No. 168 NanHai Road, 10th Avenue, TEDA, Tianjin 300457, PR China.
Wang J Wuxi AppTec (Tianjin) Co. Ltd., No. 168 NanHai Road, 10th Avenue, TEDA, Tianjin 300457, PR China.
Liang H Wuxi AppTec (Tianjin) Co. Ltd., No. 168 NanHai Road, 10th Avenue, TEDA, Tianjin 300457, PR China.

2017-11-25

Published in:

Bioorganic & medicinal chemistry letters. - 2018

Structure-Activity Relationship

English 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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