title: 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.
abstract: 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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. sean.turner@abbott.com
authors.forename: Sean C
authors.initials: SC
authors.lastname: Turner
authors.forename: William A
authors.initials: WA
authors.lastname: Carroll
authors.forename: Tammie K
authors.initials: TK
authors.lastname: White
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Coghlan
authors.forename: Char-Chang
authors.initials: CC
authors.lastname: Shieh
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Zhang
authors.forename: Ashutosh S
authors.initials: AS
authors.lastname: Parihar
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buckner
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
mesh_terms: 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
chemical_list: D000588:Amines; D001372:Aza Compounds; D007211:Indoles; D024681:Potassium Channels, Calcium-Activated; D002118:Calcium