N-Aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides:  KATP Potassium Channel Openers. Modifications on the Western Region

• Published in: Journal of medicinal chemistry Vol. 39; no. 23; pp. 4592 - 4601
• Main Authors: Ohnmacht, Cyrus J, Russell, Keith, Empfield, James R, Frank, Cathy A, Gibson, Keith H, Mayhugh, Daniel R, McLaren, Frances M, Shapiro, Howard S, Brown, Frederick J, Trainor, Diane A, Ceccarelli, Christopher, Lin, Margaret M, Masek, Brian B, Forst, Janet M, Harris, Robert J, Hulsizer, James M, Lewis, Joseph J, Silverman, Stuart M, Smith, Reed W, Warwick, Paul J, Kau, Sen T, Chun, Alexa L, Grant, Thomas L, Howe, Burton B, Li, Jack H, Trivedi, Shephali, Halterman, Tracy J, Yochim, Christopher, Dyroff, Martin C, Kirkland, M, Neilson, Kathleen L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 08-11-1996
• Subjects: Amides - chemistry; Amides - pharmacology; Amides - therapeutic use; Animals; Biological and medical sciences; Cricetinae; In Vitro Techniques; Medical sciences; Muscle Contraction; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Pharmacology. Drug treatments; Potassium Channels - agonists; Rats; Structure-Activity Relationship; Urinary Bladder - drug effects; Urinary Bladder - physiology; Urinary Incontinence - drug therapy; Urinary system; Urinary system disease; Haloalcohol; Rat; Sulfone; Hydroxyamide; Rodentia; Benzene derivatives; Ketone; In vitro; Potassium channel agonist; Pyridine derivatives; Urinary incontinence; In vivo; Vertebrata; Mammalia; Guinea pig; Structure activity relation; Urinary bladder; Animal; Enantiomer; Carboxamide; Portal vein; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960365n

A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure−activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(−) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.