A new class of anthelmintics effective against drug-resistant nematodes

Ronald Kaminsky (), Pierre Ducray, Martin Jung, Ralph Clover, Lucien Rufener, Jacques Bouvier, Sandra Schorderet Weber, Andre Wenger, Susanne Wieland-Berghausen, Thomas Goebel, Noelle Gauvry, François Pautrat, Thomas Skripsky, Olivier Froelich, Clarisse Komoin-Oka, Bethany Westlund, Ann Sluder and Pascal Mäser
Additional contact information
Ronald Kaminsky: Novartis Centre de Recherche Santé Animale
Pierre Ducray: Novartis Animal Health Inc.
Martin Jung: Novartis Centre de Recherche Santé Animale
Ralph Clover: Cambria Biosciences, Woburn, Massachusetts 01801, USA
Lucien Rufener: Novartis Centre de Recherche Santé Animale
Jacques Bouvier: Novartis Centre de Recherche Santé Animale
Sandra Schorderet Weber: Novartis Centre de Recherche Santé Animale
Andre Wenger: Novartis Centre de Recherche Santé Animale
Susanne Wieland-Berghausen: Novartis Animal Health Inc.
Thomas Goebel: Novartis Animal Health Inc.
Noelle Gauvry: Novartis Animal Health Inc.
François Pautrat: Novartis Animal Health Inc.
Thomas Skripsky: Novartis Animal Health Inc.
Olivier Froelich: Novartis Centre de Recherche Santé Animale
Clarisse Komoin-Oka: Laboratoire Central Vétérinaire de Bingerville, BP 206, Lanada, Côte d’Ivoire
Bethany Westlund: Cambria Biosciences, Woburn, Massachusetts 01801, USA
Ann Sluder: Cambria Biosciences, Woburn, Massachusetts 01801, USA
Pascal Mäser: Institute of Cell Biology, University of Bern

Nature, 2008, vol. 452, issue 7184, 176-180

Abstract: Abstract Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics—the benzimidazoles, imidazothiazoles and macrocyclic lactones—has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.

Date: 2008
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DOI: 10.1038/nature06722

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