Synthesis and SAR studies of very potent imidazopyridine antiprotozoal agents.
Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.
Biftu
Tesfaye
T
Merck Research Laboratories, Department of Medicinal Chemistry, Merck and Co., Inc, PO Box 2000, Rahway, NJ 07065, USA. Tesfaye_Biftu@merck.com
Feng
Dennis
D
Fisher
Michael
M
Liang
Gui-Bai
GB
Qian
Xiaoxia
X
Scribner
Andrew
A
Dennis
Richard
R
Lee
Shuliang
S
Liberator
Paul A
PA
Brown
Chris
C
Gurnett
Anne
A
Leavitt
Penny S
PS
Thompson
Donald
D
Mathew
John
J
Misura
Andrew
A
Samaras
Samantha
S
Tamas
Tamas
T
Sina
Joseph F
JF
McNulty
Kathleen A
KA
McKnight
Crystal G
CG
Schmatz
Dennis M
DM
Wyvratt
Matthew
M
D000821:Animal Feed; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002645:Chickens; D003048:Coccidiosis / Q000188:drug therapy; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D016786:Eimeria tenella / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009152:Mutagenicity Tests; D033661:Oocysts / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D017869:Cyclic GMP-Dependent Protein Kinases