Synthesis and biological activity of imidazopyridine anticoccidial agents: Part II.
Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.
Scribner
Andrew
A
SCYNEXIS, Inc., Discovery Chemistry, P.O. Box 12878, Research Triangle Park, NC 27709-2878, USA. andrew.scribner@scynexis.com
Dennis
Richard
R
Lee
Shuliang
S
Ouvry
Gilles
G
Perrey
David
D
Fisher
Michael
M
Wyvratt
Matthew
M
Leavitt
Penny
P
Liberator
Paul
P
Gurnett
Anne
A
Brown
Chris
C
Mathew
John
J
Thompson
Donald
D
Schmatz
Dennis
D
Biftu
Tesfaye
T
D000818:Animals; D003049:Coccidiostats / Q000138:chemical synthesis* / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004539:Eimeria / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
D003049:Coccidiostats; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017869:Cyclic GMP-Dependent Protein Kinases; C023666:pyridine