Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 1. N-Cyanoguanidine bioisosteres possessing in vivo bladder selectivity.
A structurally novel series of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel openers is described. As part of our efforts directed toward identifying novel, bladder-selective potassium channel openers (KCOs) targeted for urge urinary incontinence (UUI), we found that bioisosteric replacement of the N-cyanoguanidine moiety of pinacidil (1, Figure 1) with a diaminocyclobutenedione template afforded squaric acid analogue 2, the prototype of a novel series of K(ATP) channel openers with unique selectivity for bladder smooth muscle in vivo. Further modification of the heterocyclic ring to give substituted aryl derivatives (3) afforded potent KCOs that possessed the desired detrusor selectivity when administered orally. The effects of these potassium channel agonists on bladder contractile function was studied in vitro using isolated rat detrusor strips. Potent relaxants were evaluated in vivo in a rat model of bladder instability. Lead compounds were evaluated concomitantly in normotensive rats for their effects on mean arterial blood pressure (MAP) and heart rate as a measure of in vivo bladder selectivity. (R)-4-[3,4-Dioxo-2-(1,2, 2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzo nitrile (79) met our potency and selectivity criteria and represents an attractive development candidate for the treatment of UUI. Electrophysiological studies using isolated rat bladder detrusor myocytes have demonstrated that compound 79 produces significant hyperpolarization which is glyburide-reversed, thus consistent with the activation of K(ATP). The design, synthesis, structure-activity relationships (SAR), and pharmacological activity associated with this series of novel KCOs will be discussed.
Butera
J A
JA
Chemical Sciences, Cardiac Diseases, Urologic Diseases, Woman's Health Discovery Research, Wyeth-Ayerst Research, CN 8000, Princeton, New Jersey 08543-8000, USA. buterj@war.wyeth.com
Antane
M M
MM
Antane
S A
SA
Argentieri
T M
TM
Freeden
C
C
Graceffa
R F
RF
Hirth
B H
BH
Jenkins
D
D
Lennox
J R
JR
Matelan
E
E
Norton
N W
NW
Quagliato
D
D
Sheldon
J H
JH
Spinelli
W
W
Warga
D
D
Wojdan
A
A
Woods
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D014549:Urinary Incontinence / Q000188:drug therapy
C406344:4-(3,4-dioxo-2-(1,2,2-trimethylpropylamino)cyclobut-1-enylamino)-3-ethylbenzonitrile; D003503:Cyclobutanes; D009570:Nitriles; D015221:Potassium Channels; D011189:Potassium Chloride; D000255:Adenosine Triphosphate