N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides: KATP potassium channel openers. Modifications on the western region.
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.
Ohnmacht
C J
CJ
Department of Medicinal Chemistry, Zeneca Pharmaceuticals, Wilmington, Delaware 19897, USA.
Russell
K
K
Empfield
J R
JR
Frank
C A
CA
Gibson
K H
KH
Mayhugh
D R
DR
McLaren
F M
FM
Shapiro
H S
HS
Brown
F J
FJ
Trainor
D A
DA
Ceccarelli
C
C
Lin
M M
MM
Masek
B B
BB
Forst
J M
JM
Harris
R J
RJ
Hulsizer
J M
JM
Lewis
J J
JJ
Silverman
S M
SM
Smith
R W
RW
Warwick
P J
PJ
Kau
S T
ST
Chun
A L
AL
Grant
T L
TL
Howe
B B
BB
Neilson
K L
KL
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D006224:Cricetinae; D066298:In Vitro Techniques; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000819:agonists*; D051381:Rats; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D014549:Urinary Incontinence / Q000188:drug therapy
D000577:Amides; D015221:Potassium Channels