Structure-activity relationship of a novel class of naphthyl amide KATP channel openers.
We have discovered a novel series of N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl] amides that are potent openers of K(ATP) channels and investigated structure-activity relationships (SAR) around the 1,2-disubstituted naphthyl core. A-151892, a prototype compound of this series, was found to be a potent and efficacious potassium channel opener in vitro in transfected Kir6.2/SUR2B cells and pig bladder strips. Additionally, A-151892 was found to selectively inhibit unstable bladder contractions in vivo in an obstructed rat model of myogenic bladder function
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, IL 60064, USA. sean.turner@abbott.com
Sean C
SC
Turner
William A
WA
Carroll
Tammie K
TK
White
Michael E
ME
Brune
Steven A
SA
Buckner
Murali
M
Gopalakrishnan
Adebola
A
Fabiyi
Michael J
MJ
Coghlan
Victoria E
VE
Scott
Neil A
NA
Castle
Anthony V
AV
Daza
Ivan
I
Milicic
James P
JP
Sullivan
D018528:ATP-Binding Cassette Transporters / Q000819:agonists / Q000235:genetics; D000577:Amides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D005456:Fluorescent Dyes; D006801:Humans; D006984:Hypertrophy / Q000188:drug therapy; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009281:Naphthalenes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists* / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000819:agonists / Q000235:genetics; D013329:Structure-Activity Relationship; D064233:Sulfonylurea Receptors; D013552:Swine; D014162:Transfection; D001743:Urinary Bladder / Q000473:pathology
D018528:ATP-Binding Cassette Transporters; D000577:Amides; D005456:Fluorescent Dyes; D009281:Naphthalenes; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors