N-Arylated pyrrolidin-2-ones and morpholin-3-ones as potassium channel openers.
Based on the most stable conformation of ZD6169, a series of N-arylated derivatives of oxazolidindione (2), morpholin-3-one (3-5), piperidin-2-one (6), and pyrrolidin-2-one (7-13) was synthesized and evaluated for potassium channel opening activity. In the in-vitro assays, N-(4-benzoylphenyl)-piperidin-2-on (6) and N-(4-benzoylphenyl)-3,3-dimethyl-pyrrolidin-2-one (9) demonstrated potent and selective relaxant activity at the bladder detrusor muscle [IC50, bladder)=7.4 and 6.7 microM, respectively; IC50 ratio (portal vein/bladder)=41 and 51, respectively].
Liang
Pi-Hui
PH
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
Hsin
Ling-Wei
LW
Cheng
Chen-Yu
CY
D000577:Amides / Q000737:chemistry; D000818:Animals; D001577:Benzophenones / Q000737:chemistry; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D009025:Morpholines / Q000138:chemical synthesis / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011169:Portal Vein; D015221:Potassium Channels / Q000819:agonists / Q000187:drug effects*; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D001743:Urinary Bladder; D014549:Urinary Incontinence / Q000188:drug therapy
D000577:Amides; D001577:Benzophenones; D009025:Morpholines; D015221:Potassium Channels; D011760:Pyrrolidinones; C095007:Zeneca ZD 6169