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]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 microM, C50, portal vein = 34.5 microM). 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 microM, IC50, portal vein = 0.54 microM). The 4-bromo analogue (-)-19 (IC50, bladder = 2.0 microM, IC50, portal vein = 8.1 microM) and the 4-hydroxy analogue (-)-21 (IC50, bladder = 3.8 microM, IC50, portal vein = 75 microM) showed enhanced activity at the bladder, while maintaining unprecedented bladder selectivity in vitro. The N-benzenesulfonyl analogue (-)-22, a bioisoster of (-)-11, showed similar activity at the bladder with enhanced selectivity (IC50, bladder = 11.6 microM, IC50, portal vein = 120 microM).
Chiu
I
I
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei.
Lin
Y C
YC
Cheng
C Y
CY
Tsai
M C
MC
Yu
H C
HC
D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D019806:Cromakalim / Q000031:analogs & derivatives / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology*; D009904:Optical Rotation; D009928:Organ Specificity; D010078:Oxazines / Q000138:chemical synthesis / Q000494:pharmacology*; D010276:Parasympatholytics / Q000138:chemical synthesis / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000737:chemistry; D014549:Urinary Incontinence / Q000188:drug therapy; D014662:Vasoconstrictor Agents / Q000138:chemical synthesis / Q000494:pharmacology
D001578:Benzopyrans; D009570:Nitriles; D010078:Oxazines; D010276:Parasympatholytics; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D019806:Cromakalim