%0 Journal Article
%A Akama, Tsutomu
%A Freund, Yvonne R.
%A Berry, Pamela W.
%A Carter, David S.
%A Easom, Eric E.
%A Jarnagin, Kurt
%A Lunde, Christopher S.
%A Plattner, Jacob J.
%A Rock, Fernando
%A Stefanakis, Rianna
%A Fischer, Chelsea
%A Bulman, Christina A.
%A Lim, Kee Chong
%A Suzuki, Brian M.
%A Tricoche, Nancy
%A Mansour, Abdelmoneim
%A DiCosty, Utami
%A McCall, Scott
%A Carson, Ben
%A McCall, John W.
%A McKerrow, James
%A Hübner, Marc P.
%A Specht, Sabine
%A Hoerauf, Achim
%A Lustigman, Sara
%A Sakanari, Judy A.
%A Jacobs, Robert T.
%D 2020
%T Macrofilaricidal Benzimidazole–Benzoxaborole
Hybrids as an Approach to the Treatment of River Blindness: Part 1.
Amide Linked Analogs
%U https://acs.figshare.com/articles/journal_contribution/Macrofilaricidal_Benzimidazole_Benzoxaborole_Hybrids_as_an_Approach_to_the_Treatment_of_River_Blindness_Part_1_Amide_Linked_Analogs/11595288
%R 10.1021/acsinfecdis.9b00396.s001
%2 https://acs.figshare.com/ndownloader/files/20987442
%K . pahangi
%K river blindness
%K Brugia malayi
%K B . pahangi
%K amide linker
%K dosing period
%K Mongolian gerbils
%K animal models
%K subcutaneously
%K flubendazole
%K series
%K measurement
%K evaluation
%K Litomosoides sigmodontis worms
%K disease onchocerciasis
%K Compound 8
%K dependence
%K Benzimidazole
%K Part 1. Amide
%K Hybrid
%K Approach
%K benzimidazole
%K suspension
%K mg
%K exhibit
%K 14 days
%K River Blindness
%K filariasi
%K pharmacokinetic properties
%K Onchocerca volvulus
%K sacrifice
%K molecule
%K Macrofilaricidal
%K plasma levels
%K exposure
%K filarial nematode
%K 28 days
%K Analog
%X A series of benzimidazole–benzoxaborole
hybrid molecules
linked via an amide linker are described that exhibit good in vitro activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis,
also known as river blindness. The lead identified in this series, 8a (AN8799), was found to have acceptable pharmacokinetic
properties to enable evaluation in animal models of human filariasis.
Compound 8a was effective in killing Brugia malayi, B. pahangi, and Litomosoides sigmodontis worms present in Mongolian gerbils when dosed subcutaneously as
a suspension at 100 mg/kg/day for 14 days but not when dosed orally
at 100 mg/kg/day for 28 days. The measurement of plasma levels of 8a at the end of the dosing period and at the time of sacrifice
revealed an interesting dependence of activity on the extended exposure
for both 8a and the positive control, flubendazole.
%I ACS Publications