Prodrugs of N-dicarboximide derivatives of the rat selective toxicant norbormide.
Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either its unpleasant 'taste' or rapid onset of effects. A series of NRB-derived prodrugs were prepared in an effort to 'mask' this acute response. Their synthesis and biological evaluation (in vitro vasoconstrictory activity, in vitro hydrolytic and enzymatic stability and lethality/palatability in vivo) is described. Prodrug 2 displayed the most promising profile with respect to a delay in the onset of symptoms and was subsequently demonstrated to be significantly more palatable to rats. Moreover, prodrug 25 was found to be largely accepted by rats in a choice trial, resulting in high mortality.
School of Chemical Sciences, The University of Auckland, New Zealand. d.rennison@auckland.ac.nz
David
D
Rennison
Olivia
O
Laita
Daniel
D
Conole
Morgan
M
Jay-Smith
Jan
J
Knauf
Sergio
S
Bova
Maurizio
M
Cavalli
Brian
B
Hopkins
Darwin S
DS
Linthicum
Margaret A
MA
Brimble
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D006868:Hydrolysis; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D008099:Liver / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009636:Norbornanes / Q000737:chemistry* / Q000633:toxicity; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D007094:Imides; D009636:Norbornanes; D011355:Prodrugs; C005321:norbormide
Norbormide; Prodrug; Rat toxicant; Raticide; Rodenticide