Stress urinary incontinence (SUI) is a common type of lower urinary tract control problem in women and can significantly impact the quality of life. SUI occurs when abdominal pressure or stress is placed on urethral sphincter or pelvic floor muscles damaged from obsterical trauma or obesity. α1L-Adorenoceptor agonists are known to play an important role for contraction of urethra and expected as a novel treatment for SUI. We began to explore potent α1L–adorenoceptor agonists from MK017 reported by nippon chemiphar using ligand based drug design strategy. We discovered that tetrahydroquinoline derivatives exhibited high α1L–adorenoceptor agonist activity (EC50 up to 3.3 nM, noradrenaline : EC50 = 1100 nM) and magnus activity for rat bladder neck contraction. Along with the synthesis of these derivatives, their structure-activity relationships are described.

Discovery of potent α1L-adrenoceptor agonists: Design and synthesis of bicyclic derivatives

249th National Meeting (2015)

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