Novel and potent transforming growth factor beta type I receptor kinase domain inhibitor: 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolines.
A novel series of 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolines was synthesized and their TbetaR-1 inhibitory, p38 MAPK inhibitory, and TbetaR-1-dependent cellular activity were evaluated. Compound 5a was found to be a highly potent in the enzyme assay and TbetaR-1-dependent cellular assays. In addition, dimer (4g), with a urea linker, shows a similar enzyme and cellular activity despite a bulky substitution.
Li
Hong-yu
HY
Discovery Chemistry Research, Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. li_hong-yu@lilly.com
Wang
Yan
Y
Yan
Lei
L
Campbell
Robert M
RM
Anderson
Bryan D
BD
Wagner
Jill R
JR
Yingling
Jonathan M
JM
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D019281:Dimerization; D006801:Humans; D020128:Inhibitory Concentration 50; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D011720:Pyrazoles; D011758:Pyrroles; D011804:Quinolines; D018125:Receptors, Transforming Growth Factor beta; D014508:Urea; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I