Effects of substitution on 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4- azacyclopenta[b]naphthalene-1,8-dione, a dihydropyridine ATP-sensitive potassium channel opener.
Structure-activity relationships were investigated on the tricyclic dihydropyridine (DHP) KATP openers 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (6) and 10-(3-bromo-4-fluorophenyl)-9,10-dihydro-1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (65). Substitution off the core of the DHP, absolute stereochemistry, and aromatic substitution were evaluated for KATP channel activity using Ltk- cells stably transfected with the Kir6.2/SUR2B exon 17- splice variant and in an electrically stimulated pig bladder strip assay. A select group of compounds was evaluated for in vitro inhibition of spontaneous bladder contractions. Several compounds were found to have the unique characteristic of partial efficacy in both the cell-based and electrically stimulated bladder strip assays but full efficacy in inhibiting spontaneous bladder strip contractions. For compound 23b, this profile was mirrored in vivo where it was fully efficacious in inhibiting spontaneous myogenic bladder contractions but only partially able to reduce neurogenically mediated reflex bladder contractions.
Altenbach
Robert J
RJ
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6123, USA. Robert.j.altenbach@abbott.com
Brune
Michael E
ME
Buckner
Steven A
SA
Coghlan
Michael J
MJ
Daza
Anthony V
AV
Fabiyi
Adebola
A
Gopalakrishnan
Murali
M
Henry
Rodger F
RF
Khilevich
Albert
A
Kort
Michael E
ME
Milicic
Ivan
I
Scott
Victoria E
VE
Smith
Jamie C
JC
Whiteaker
Kristi L
KL
Carroll
William A
WA
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000737:chemistry*; D004558:Electric Stimulation; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D051379:Mice; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D000099161:Kcnj11 Channel
D000255:Adenosine Triphosphate; D001372:Aza Compounds; D004095:Dihydropyridines; D006575:Heterocyclic Compounds, 3-Ring; D009281:Naphthalenes; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel; C516225:9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta(b)naphthalene-1,8-dione