Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.
Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.
Sawyer
J Scott
JS
Discovery Chemistry Research and Technology, The Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. jss@lilly.com
Anderson
Bryan D
BD
Beight
Douglas W
DW
Campbell
Robert M
RM
Jones
Michael L
ML
Herron
David K
DK
Lampe
John W
JW
McCowan
Jefferson R
JR
McMillen
William T
WT
Mort
Nicholas
N
Parsons
Stephen
S
Smith
Edward C R
EC
Vieth
Michal
M
Weir
Leonard C
LC
Yan
Lei
L
Zhang
Faming
F
Yingling
Jonathan M
JM
D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008907:Mink; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018411:Spodoptera; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases
D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases