title: Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.
abstract: We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TbetaR-I receptor kinase domain.
authors.affiliation: Discovery Chemistry Research and Technology, The Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. jss.dcrt@lilly.com
authors.forename: J Scott
authors.initials: JS
authors.lastname: Sawyer
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Beight
authors.forename: Karen S
authors.initials: KS
authors.lastname: Britt
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Robert M
authors.initials: RM
authors.lastname: Campbell
authors.forename: Theodore
authors.initials: T
authors.lastname: Goodson
authors.forename: David K
authors.initials: DK
authors.lastname: Herron
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Li
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: Jill R
authors.initials: JR
authors.lastname: Wagner
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: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D018125:Receptors, Transforming Growth Factor beta; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I