Details

Autor(en) / Beteiligte

• Taylor, Mark J
• von Geldern, Thomas W
• Ford, Louise
• Hübner, Marc P
• Marsh, Kennan
• Johnston, Kelly L
• Sjoberg, Hanna T
• Specht, Sabine
• Pionnier, Nicolas
• Tyrer, Hayley E
• Clare, Rachel H
• Cook, Darren A N
• Murphy, Emma
• Steven, Andrew
• Archer, John
• Bloemker, Dominique
• Lenz, Franziska
• Koschel, Marianne
• Ehrens, Alexandra
• Metuge, Haelly M
• Chunda, Valerinne C
• Ndongmo Chounna, Patrick W
• Njouendou, Abdel J
• Fombad, Fanny F
• Carr, Robert
• Morton, Howard E
• Aljayyoussi, Ghaith
• Hoerauf, Achim
• Wanji, Samuel
• Kempf, Dale J
• Turner, Joseph D
• Ward, Stephen A

Titel

Preclinical development of an oral anti- Wolbachia macrolide drug for the treatment of lymphatic filariasis and onchocerciasis

Ist Teil von

• Science translational medicine, 2019-03, Vol.11 (483)

Ort / Verlag

United States

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against This bacterial endosymbiont is required for filarial worm viability and fertility and is a validated target for macrofilaricidal drugs. Medicinal chemistry was undertaken to develop tylosin A analogs with improved oral bioavailability. Two analogs, A-1535469 and A-1574083, were selected. Their efficacy was tested against the gold-standard second-generation tetracycline antibiotics, doxycycline and minocycline, in mouse and gerbil infection models of lymphatic filariasis ( and ) and onchocerciasis ( ). A 1- or 2-week course of oral A-1535469 or A-1574083 provided >90% depletion from nematodes in infected animals, resulting in a block in embryogenesis and depletion of microfilarial worm loads. The two analogs delivered comparative or superior efficacy compared to a 3- to 4-week course of doxycycline or minocycline. A-1574083 (now called ABBV-4083) was selected for further preclinical testing. Cardiovascular studies in dogs and toxicology studies in rats and dogs revealed no adverse effects at doses (50 mg/kg) that achieved plasma concentrations >10-fold above the efficacious concentration. A-1574083 (ABBV-4083) shows potential as an anti- macrolide with an efficacy, pharmacology, and safety profile that is compatible with a short-term oral drug course for treating lymphatic filariasis and onchocerciasis.