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

Optically active N-acyl-5,5-dimethyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyran o[3,4-b][1,4]oxazine-9-carbonitriles 2-22 were synthesized as rigid analogu es of cromakalim. The (4aR,10br)-N-benzoyl derivative (-)-11 was identified as a bladder-selective KCO (IC50, (bladder) = 82 muM, IC50, (portal vein) = 34.5 muM). Among the analogues of 11 with substitution on the benzoyl moi ety, the 3-methyl analogue (-)-14 showed highly potent and selective activi ty at portal vein (IC50, (bladder) = 279 muM, IC50, (portal vein) = 0.54 mu M). The 4-bromo analogue (-)-19 (IC50, (bladder) = 2.0 muM, IC50, (portal v ein) = 8.1 muM) and the 4-hydroxy analogue (-)-21 (IC50, (bladder) = 3.8 mu M, IC50, portal vein = 75 muM) showed enhanced activity at the bladder, whi le maintaining unprecedented bladder selectivity in vitro. The N-benzenesul fonyl analogue (-)-22, a bioisoster of (-)-11, showed similar activity at t he bladder with enhanced selectivity (IC50, bladder = 116 muM, IC50, portal vein = 120 muM) (C) 2001 Elsevier Science Ltd. All rights reserved.