N-Acyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyrano-[3,4-b][1,4]oxazine-9-carbonitriles as bladder-selective potassium channel openers Original Research Article

Optically active N-acyl-5,5-dimethyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyrano[3,4-b][1,4]oxazine-9-carbonitriles 2–22 were synthesized as rigid analogues of cromakalim. The (4aR,10bR)-N-benzoyl derivative (−)-11 was identified as a bladder-selective KCO (IC50, bladder=8.2 μM, IC50, portal vein=34.5 μM). Among the analogues of 11 with substitution on the benzoyl moiety, the 3-methyl analogue (−)-14 showed highly potent and selective activity at portal vein (IC50, bladder=279 μM, IC50, portal vein=0.54 μM). The 4-bromo analogue (−)-19 (IC50, bladder=2.0 μM, IC50, portal vein=8.1 μM) and the 4-hydroxy analogue (−)-21 (IC50, bladder=3.8 μM, IC50, portal vein=75 μM) showed enhanced activity at the bladder, while maintaining unprecedented bladder selectivity in vitro. The N-benzenesulfonyl analogue (−)-, a bioisoster of (−)-11, showed similar activity at the bladder with enhanced selectivity (IC50, bladder=11.6 μM, IC50, portal vein=120 μM).