The discovery of a new class of large-conductance Ca2+-activated K+ channel opener targeted for overactive bladder: synthesis and structure-activity relationships of 2-amino-4-azaindoles.
2-Amino-4-azaindoles have been identified as a structurally novel class of BK(Ca) channel openers. Their synthesis from 2-chloro-3-nitropyridine is described together with their in vitro properties assessed by 86Rb(+) efflux and whole-cell patch-clamp assays using HEK293 cells stably transfected with the BK(Ca) alpha subunit. In vitro functional characterization of BK(Ca) channel opening activity was also assessed by measurement of relaxation of smooth muscle tissue strips obtained from Landrace pig bladders. The preliminary SAR data indicate the importance of steric bulk around the 2-amino substituent.
Turner
Sean C
SC
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. sean.turner@abbott.com
Carroll
William A
WA
White
Tammie K
TK
Gopalakrishnan
Murali
M
Coghlan
Michael J
MJ
Shieh
Char-Chang
CC
Zhang
Xu-Feng
XF
Parihar
Ashutosh S
AS
Buckner
Steven A
SA
Milicic
Ivan
I
Sullivan
James P
JP
D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine; D014162:Transfection; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D001745:Urinary Bladder Diseases / Q000188:drug therapy; D014555:Urination Disorders / Q000188:drug therapy
D000588:Amines; D001372:Aza Compounds; D007211:Indoles; D024681:Potassium Channels, Calcium-Activated; D002118:Calcium