Basic Information
ID: ALA1129399
Journal: J Med Chem
Title: N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides: KATP potassium channel openers. Modifications on the western region.
Authors: Ohnmacht CJ, Russell K, Empfield JR, Frank CA, Gibson KH, Mayhugh DR, McLaren FM, Shapiro HS, Brown FJ, Trainor DA, Ceccarelli C, Lin MM, Masek BB, Forst JM, Harris RJ, Hulsizer JM, Lewis JJ, Silverman SM, Smith RW, Warwick PJ, Kau ST, Chun AL, Grant TL, Howe BB, Neilson KL.
Abstract: 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.
CiteXplore: 8917648
DOI: 10.1021/jm960365n
Patent ID: ┄
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