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Macrofilaricidal Benzimidazole–Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 2. Ketone Linked Analogs

Authors
  • Carter, David S.1
  • Jacobs, Robert T.1
  • Freund, Yvonne R.1
  • Berry, Pamela W.1
  • Akama, Tsutomu1
  • Easom, Eric E.1
  • Lunde, Christopher S.1
  • Rock, Fernando1
  • Stefanakis, Rianna1
  • McKerrow, James2
  • Fischer, Chelsea3
  • Bulman, Christina A.3
  • Lim, Kee Chong3
  • Suzuki, Brian M.2
  • Tricoche, Nancy4
  • Sakanari, Judy A.3
  • Lustigman, Sara4
  • Plattner, Jacob J.1
  • 1 Anacor Pharmaceuticals, Inc., United States , (United States)
  • 2 University of California San Diego, United States , (United States)
  • 3 University of California San Francisco, United States , (United States)
  • 4 New York Blood Center, United States , (United States)
Type
Published Article
Journal
ACS Infectious Diseases
Publisher
American Chemical Society
Publication Date
Dec 26, 2019
Volume
6
Issue
2
Pages
180–185
Identifiers
DOI: 10.1021/acsinfecdis.9b00397
PMID: 31876143
PMCID: PMC7026882
Source
PubMed Central
Keywords
License
Unknown

Abstract

The optimization of a series of benzimidazole–benzoxaborole hybrid molecules linked via a ketone that exhibit good activity against Onchocerca volvulus , a filarial nematode responsible for the disease onchocerciasis, also known as river blindness, is described. The lead identified in this series, 21 (AN15470), was found to have acceptable pharmacokinetic properties to enable an evaluation following oral dosing in an animal model of onchocerciasis. Compound 21 was effective in killing worms implanted in Mongolian gerbils when dosed orally as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 7 days.

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