title: Potent Kv1.3 inhibitors from correolide-modification of the C18 position.
abstract: Kv1.3, the voltage-gated potassium channel in human T cells, represents a new target for treating immunosuppression and autoimmune diseases. Correolide (1), a pentacyclic natural product, is a potent and selective Kv1.3 channel blocker. Simplification of correolide via removal of its E-ring generates enone 4, whose modification produced a new series of tetracyclic Kv1.3 blockers. The structure-activity relationship for this class of compounds in two functional assays, Rb_Kv and human T cell proliferation, is presented herein. The most potent analog 43 is 15-fold more potent than correolide as inhibitor of human T cell proliferation.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. bao_jianming@merck.com
authors.forename: Jianming
authors.initials: J
authors.lastname: Bao
authors.forename: Shouwu
authors.initials: S
authors.lastname: Miao
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kotliar
authors.forename: Robert K
authors.initials: RK
authors.lastname: Baker
authors.forename: George A
authors.initials: GA
authors.lastname: Doss
authors.forename: John P
authors.initials: JP
authors.lastname: Felix
authors.forename: Randal M
authors.initials: RM
authors.lastname: Bugianesi
authors.forename: Robert S
authors.initials: RS
authors.lastname: Slaughter
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.forename: Sookhee N
authors.initials: SN
authors.lastname: Ha
authors.forename: Laurie
authors.initials: L
authors.lastname: Castonguay
authors.forename: Gloria C
authors.initials: GC
authors.lastname: Koo
authors.forename: Kashmira
authors.initials: K
authors.lastname: Shah
authors.forename: Marty S
authors.initials: MS
authors.lastname: Springer
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Staruch
authors.forename: William H
authors.initials: WH
authors.lastname: Parsons
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Rupprecht
mesh_terms: D001681:Biological Assay; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D051664:Kv1.3 Potassium Channel; D008958:Models, Molecular; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; C496973:KCNA3 protein, human; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D014315:Triterpenes; C118657:correolide