Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 1. N-cyanoguanidine bioisosteres possessing in vivo bladderselectivity

A structurally novel series of adenosine 5'-triphosphate-sensitive potassiu m (K-ATP) channel openers is described. As part of our efforts directed tow ard identifying novel, bladder-selective potassium channel openers (KCOs) t argeted for urge urinary incontinence (UUI), we found that bioisosteric rep lacement of the N-cyanoguanidine moiety of pinacidil (1, Figure 1) with a d iaminocyclobutenedione template afforded squaric acid analogue 2, the proto type of a novel series of K-ATP channel openers with unique selectivity for bladder smooth muscle in vivo. Further modification of the heterocyclic ri ng to give substituted aryl derivatives (3) afforded potent KCOs that posse ssed the desired detrusor selectivity when administered orally. The effects of these potassium channel agonists on bladder contractile function was st udied in vitro using isolated rat detrusor strips. Potent relaxants were ev aluated in vivo in a rat model of bladder instability. Lead compounds were evaluated concomitantly in normotensive rats for their effects on mean arte rial blood pressure (MAP) and heart rate as a measure of in vivo bladder se lectivity. (R)-4-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl amino]-3-ethyl-benzonitrile (79) met our potency and selectivity criteria a nd 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 w hich is glyburide-reversed, thus consistent with the activation of KATP The design, synthesis, structure-activity relationships (SAR), and pharmacolog ical activity associated with this series of novel KCOs will be discussed.