Synthesis and SAR of 2,3-diarylpyrrole inhibitors of parasite cGMP-dependent protein kinase as novel anticoccidial agents.
Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.
Biftu
Tesfaye
T
Merck Research Laboratories, Department of Medicinal Chemistry, Merck and Co., P.O. Box 2000, Rahway, NJ 07065-0900, USA. tesfaye_biftu@merck.com
Feng
Dennis
D
Ponpipom
Mitree
M
Girotra
Narindar
N
Liang
Gui-Bai
GB
Qian
Xiaoxia
X
Bugianesi
Robert
R
Simeone
Joseph
J
Chang
Linda
L
Gurnett
Anne
A
Liberator
Paul
P
Dulski
Paula
P
Leavitt
Penny Sue
PS
Crumley
Tami
T
Misura
Andrew
A
Murphy
Terence
T
Rattray
Sandra
S
Samaras
Samantha
S
Tamas
Tamas
T
Mathew
John
J
Brown
Christine
C
Thompson
Don
D
Schmatz
Dennis
D
Fisher
Michael
M
Wyvratt
Matthew
M
D000818:Animals; D001682:Biological Availability; D002645:Chickens; D003048:Coccidiosis / Q000188:drug therapy; D003049:Coccidiostats / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004539:Eimeria; D006207:Half-Life; D020128:Inhibitory Concentration 50; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D003049:Coccidiostats; D015800:Protozoan Proteins; D011758:Pyrroles; D017869:Cyclic GMP-Dependent Protein Kinases