title: Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.
abstract: 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.
authors.affiliation: 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
authors.forename: J Scott
authors.initials: JS
authors.lastname: Sawyer
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Beight
authors.forename: Robert M
authors.initials: RM
authors.lastname: Campbell
authors.forename: Michael L
authors.initials: ML
authors.lastname: Jones
authors.forename: David K
authors.initials: DK
authors.lastname: Herron
authors.forename: John W
authors.initials: JW
authors.lastname: Lampe
authors.forename: Jefferson R
authors.initials: JR
authors.lastname: McCowan
authors.forename: William T
authors.initials: WT
authors.lastname: McMillen
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mort
authors.forename: Stephen
authors.initials: S
authors.lastname: Parsons
authors.forename: Edward C R
authors.initials: EC
authors.lastname: Smith
authors.forename: Michal
authors.initials: M
authors.lastname: Vieth
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Weir
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.forename: Faming
authors.initials: F
authors.lastname: Zhang
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Yingling
mesh_terms: 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
chemical_list: 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