Potent Kv1.3 inhibitors from correolide-modification of the C18 position.
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.
Bao
Jianming
J
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. bao_jianming@merck.com
Miao
Shouwu
S
Kayser
Frank
F
Kotliar
Andrew J
AJ
Baker
Robert K
RK
Doss
George A
GA
Felix
John P
JP
Bugianesi
Randal M
RM
Slaughter
Robert S
RS
Kaczorowski
Gregory J
GJ
Garcia
Maria L
ML
Ha
Sookhee N
SN
Castonguay
Laurie
L
Koo
Gloria C
GC
Shah
Kashmira
K
Springer
Marty S
MS
Staruch
Mary Jo
MJ
Parsons
William H
WH
Rupprecht
Kathleen M
KM
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*
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