A new class of anthelmintics effective against drug-resistant nematodes.
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.
Kaminsky
Ronald
R
Novartis Centre de Recherche Santé Animale, CH-1566 St Aubin (FR), Switzerland. ronald.kaminsky@novartis.com
Ducray
Pierre
P
Jung
Martin
M
Clover
Ralph
R
Rufener
Lucien
L
Bouvier
Jacques
J
Weber
Sandra Schorderet
SS
Wenger
Andre
A
Wieland-Berghausen
Susanne
S
Goebel
Thomas
T
Gauvry
Noelle
N
Pautrat
François
F
Skripsky
Thomas
T
Froelich
Olivier
O
Komoin-Oka
Clarisse
C
Westlund
Bethany
B
Sluder
Ann
A
Mäser
Pascal
P
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
C528080:ACR-23 protein, C elegans; D000871:Anthelmintics; D029742:Caenorhabditis elegans Proteins; D011978:Receptors, Nicotinic; D000607:Aminoacetonitrile