Guanidine - A novel bioisosteric replacement of the /V-cyanoguanidine moiety in 18 (pinacidil) with a 1,2-diaminocyclobutene-3,4-dione template has been described which led to a series of bladder-selective KATP openers as exemplified by compound 19 (22). Subsequent optimization of the metabolic properties of 19 resulted in the discovery of 20, which is 166-fold selective for bladder effects versus hemodynamic effects, and is currently under clinical evaluation for the treatment of urge urinary incontinence (23).

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