Discovery of novel isothiazole inhibitors of the TrkA kinase: structure-activity relationship, computer modeling, optimization, and identification of highly potent antagonists.
The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.
Lippa
Blaise
B
Pfizer Inc., PGRD Groton, MS-8220-2203 Eastern Point Rd., Groton, CT 06340, USA. blaise.lippa@pfizer.com
Morris
Joel
J
Corbett
Matthew
M
Kwan
Tricia A
TA
Noe
Mark C
MC
Snow
Sheri L
SL
Gant
Thomas G
TG
Mangiaracina
Melchiorra
M
Coffey
Heather A
HA
Foster
Barbara
B
Knauth
Elisabeth A
EA
Wessel
Matthew D
MD
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D020917:Receptor, trkA / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013844:Thiazoles; D020917:Receptor, trkA