Synthesis and bladder smooth muscle relaxing properties of substituted 3-amino-4-aryl-(and aralkyl-)cyclobut-3-ene-1,2-diones.

We have reported on the design, synthesis, and biological characterization of (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile (1), a novel, potent, and selective adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel opener with potential utility for the treatment of urge urinary incontinence (UUI). Excising the aniline-derived nitrogen atom of 1 or replacing it with an aralkyl group, led to bladder smooth muscle relaxant chemotypes 3 and 4, respectively. Prototype compounds in these series were found to produce significant increases in an iberiotoxin (IbTx)-sensitive hyperpolarizing current, thus suggesting that these relatively modest structural modifications resulted in a switch in the mechanism of action of these smooth muscle relaxants from K(ATP) channel openers to activators of the large-conductance Ca2+-activated potassium channel (BK(Ca)).

Synthesis and potassium channel opening activity of substituted 10H-benzo[4,5]furo[3,2-b]indole-and 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids.

Compounds in a structurally novel series of substituted 10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acids and related 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids were prepared and shown to possess potent, bladder-selective smooth muscle relaxant properties and thus are potentially useful for the treatment of urge urinary incontinence. Electrophysiological studies using rat detrusor myocytes have demonstrated that prototype compound 7 produces a significant increase in hyperpolarizing current, which is iberiotoxin (IbTx)-reversed, thus consistent with activation of the large-conductance Ca(2+)-activated potassium channel (BK(Ca)).

Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 2. Selective and potent benzylamino cyclobutenediones.

A novel series of benzylamine, potassium channel openers (KCOs) is presented as part of our program toward designing new, bladder-selective compounds for the treatment of urge urinary incontinence (UUI). We have found that the in vitro potency of (R)-4-[3,4-dioxo-2-(1,2, 2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzo nitrile 1 in the relaxation of precontracted rat detrusor strips can also be obtained with cyanobenzylamine derivative 4 (IC(50) = 0.29 microM) (Figure 3).

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.

Comparison of the potassium channel openers, WAY-133537, ZD6169, and celikalim on isolated bladder tissue and In vivo bladder instability in rat.

The effects of the ATP-dependent potassium channel agonists ZD6169, celikalim, and WAY-133537 on bladder contractile function were examined in vitro on isolated bladder strips and in vivo on spontaneous bladder contractions. All three compounds produced a concentration-dependent relaxation of isolated rat detrusor strips (IC50 values = 0.93, 0.