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
Turner
Sean C
SC
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, IL 60064, USA. sean.turner@abbott.com
Carroll
William A
WA
White
Tammie K
TK
Brune
Michael E
ME
Buckner
Steven A
SA
Gopalakrishnan
Murali
M
Fabiyi
Adebola
A
Coghlan
Michael J
MJ
Scott
Victoria E
VE
Castle
Neil A
NA
Daza
Anthony V
AV
Milicic
Ivan
I
Sullivan
James P
JP
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