title: A new class of anthelmintics effective against drug-resistant nematodes.
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.
authors.affiliation: Novartis Centre de Recherche Santé Animale, CH-1566 St Aubin (FR), Switzerland. ronald.kaminsky@novartis.com
authors.forename: Ronald
authors.initials: R
authors.lastname: Kaminsky
authors.forename: Pierre
authors.initials: P
authors.lastname: Ducray
authors.forename: Martin
authors.initials: M
authors.lastname: Jung
authors.forename: Ralph
authors.initials: R
authors.lastname: Clover
authors.forename: Lucien
authors.initials: L
authors.lastname: Rufener
authors.forename: Jacques
authors.initials: J
authors.lastname: Bouvier
authors.forename: Sandra Schorderet
authors.initials: SS
authors.lastname: Weber
authors.forename: Andre
authors.initials: A
authors.lastname: Wenger
authors.forename: Susanne
authors.initials: S
authors.lastname: Wieland-Berghausen
authors.forename: Thomas
authors.initials: T
authors.lastname: Goebel
authors.forename: Noelle
authors.initials: N
authors.lastname: Gauvry
authors.forename: François
authors.initials: F
authors.lastname: Pautrat
authors.forename: Thomas
authors.initials: T
authors.lastname: Skripsky
authors.forename: Olivier
authors.initials: O
authors.lastname: Froelich
authors.forename: Clarisse
authors.initials: C
authors.lastname: Komoin-Oka
authors.forename: Bethany
authors.initials: B
authors.lastname: Westlund
authors.forename: Ann
authors.initials: A
authors.lastname: Sluder
authors.forename: Pascal
authors.initials: P
authors.lastname: Mäser
mesh_terms: D000375:Aging; D000595:Amino Acid Sequence; D000607:Aminoacetonitrile / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000145:classification* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D002418:Cattle Diseases / Q000188:drug therapy / Q000469:parasitology; D004351:Drug Resistance / Q000235:genetics; D007814:Larva / Q000187:drug effects / Q000235:genetics; D008969:Molecular Sequence Data; D009348:Nematoda / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D010273:Parasitic Diseases, Animal / Q000188:drug therapy / Q000469:parasitology*; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012756:Sheep / Q000469:parasitology; D012757:Sheep Diseases / Q000188:drug therapy / Q000469:parasitology
chemical_list: C528080:ACR-23 protein, C elegans; D000871:Anthelmintics; D029742:Caenorhabditis elegans Proteins; D011978:Receptors, Nicotinic; D000607:Aminoacetonitrile