title: Novel indolylindazolylmaleimides as inhibitors of protein kinase C-beta: synthesis, biological activity, and cardiovascular safety.
abstract: Novel indolylindazolylmaleimides were synthesized and examined for kinase inhibition. We identified low-nanomolar inhibitors of PKC-beta with good to excellent selectivity vs other PKC isozymes and GSK-3beta. In a cell-based functional assay, 8f and 8i effectively blocked IL-8 release induced by PKC-betaII (IC(50) = 20-25 nM). In cardiovascular safety assessment, representative lead compounds bound to the hERG channel with high affinity, potently inhibited ion current in a patch-clamp experiment, and caused a dose-dependent increase of QT(c) in guinea pigs.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA. hzhang@prdus.jnj.com
authors.forename: Han-Cheng
authors.initials: HC
authors.lastname: Zhang
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Derian
authors.forename: David F
authors.initials: DF
authors.lastname: McComsey
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: White
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Leonard R
authors.initials: LR
authors.lastname: Hecker
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Michael F
authors.initials: MF
authors.lastname: Addo
authors.forename: Diane
authors.initials: D
authors.lastname: Croll
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Eckardt
authors.forename: Charles E
authors.initials: CE
authors.lastname: Smith
authors.forename: Quan
authors.initials: Q
authors.lastname: Li
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Cheung
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Conway
authors.forename: Stuart
authors.initials: S
authors.lastname: Emanuel
authors.forename: Keith T
authors.initials: KT
authors.lastname: Demarest
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000818:Animals; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry; D000071679:Glycogen Synthase Kinase 3 beta; D006168:Guinea Pigs; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D016209:Interleukin-8 / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008133:Long QT Syndrome / Q000139:chemically induced; D008301:Maleimides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry; D064546:Protein Kinase C beta; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007191:Indazoles; D007211:Indoles; D016209:Interleukin-8; D007527:Isoenzymes; C000606913:KCNH2 protein, human; D008301:Maleimides; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D038362:Glycogen Synthase Kinase 3