Carter DS et al. (2019) ACS Infect Dis "Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness. Part 2. Ketone Linked Analogs."

Lim KC, Tricoche N, Sakanari J, Bulman C, Akama T, Carter DS, Plattner JJ, Rock FL, Freund Y, Suzuki BM, Lustigman S, Jacobs RT, Easom EE, Lunde CS, McKerrow JH, Fischer C, Berry P, Stefanakis R

[ACS Infect Dis, 2019]

Optimization of a series of benzimidazole-benzoxaborole hybrid molecules linked via a ketone are described that exhibit good activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as River Blindness. The lead identified in this series, AN15470, was found to have acceptable pharmacokinetic properties to enable evaluation following oral dosing in an animal model of onchocerciasis. AN15470 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.

Akama T et al. (2019) ACS Infect Dis "Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness. Part 1. Amide Linked Analogs."

Jacobs RT, Carter DS, Hubner MP, Carson B, Fischer C, Mansour A, Lustigman S, Specht S, Jarnagin K, McCall S, Akama T, McCall JW, Lim KC, Plattner JJ, McKerrow JH, Rock F, Berry P, Bulman C, Stefanakis R, Easom EE, Hoerauf A, DiCosty U, Lunde CS, Tricoche N, Suzuki BM, Freund YT, Sakanari J

[ACS Infect Dis, 2019]

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, 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. 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 extended exposure for both 8a and the positive control, flubendazole.

Jacobs RT et al. (2019) J Med Chem "Boron-Pleuromutilins as Anti-Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis."

Guimaraes AF, Lunde CS, Myhill L, Taylor MJ, Hubner MP, Lenz F, Rock F, Xia Y, Ehrens A, Steven A, Bakowski MA, Hernandez V, Jacobs RT, Gamble J, Halladay J, McNamara C, Ford L, Clare R, Cook DAN, Tyrer H, Plattner JJ, Freund YR, Turner JD, Berry P, Stefanakis R, Frohberger SJ, Carter DS, Johnston KL, Ward SA, Easom EE, Cassidy A, Hoerauf A, Koschel M, Li X

[J Med Chem, 2019]

A series of pleuromutilins modified by introduction of a boron-containing heterocycle on C(14) of the polycyclic core are described. These analogs were found to be potent anti-Wolbachia antibiotics, and as such, may be useful in the treatment of filarial infections caused by Onchocherca volvulus, resulting in Onchocerciasis or river blindness, or Wuchereria bancrofti and Brugia malayi and related parasitic nematodes resulting in lymphatic filariasis. These two important Neglected Tropical diseases (NTDs) disproportionately impact patients in the developing world. The lead preclinical candidate compound containing a 7-fluoro-6-oxybenzoxaborole (15, AN11251) was shown to have good in vitro anti-Wolbachia activity and physicochemical and pharmacokinetic properties providing high exposure in plasma. The lead was effective in reducing the Wolbachia load in filarial worms following oral administration to mice.