Synthesis and bladder smooth muscle relaxing properties of substituted 3-amino-4-aryl-(and aralkyl-)cyclobut-3-ene-1,2-diones.
We have reported on the design, synthesis, and biological characterization of (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile (1), a novel, potent, and selective adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel opener with potential utility for the treatment of urge urinary incontinence (UUI). Excising the aniline-derived nitrogen atom of 1 or replacing it with an aralkyl group, led to bladder smooth muscle relaxant chemotypes 3 and 4, respectively. Prototype compounds in these series were found to produce significant increases in an iberiotoxin (IbTx)-sensitive hyperpolarizing current, thus suggesting that these relatively modest structural modifications resulted in a switch in the mechanism of action of these smooth muscle relaxants from K(ATP) channel openers to activators of the large-conductance Ca2+-activated potassium channel (BK(Ca)). We report herein the syntheses and biological evaluation of a series of substituted 3-amino-4-aryl-(and aralkyl-)cyclobut-3-ene-1,2-diones.
Butera
John A
JA
Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. buteraj@wyeth.com
Jenkins
Douglas J
DJ
Lennox
Joseph R
JR
Sheldon
Jeffrey H
JH
Norton
N Wesley
NW
Warga
Dawn
D
Argentieri
Thomas M
TM
D003503:Cyclobutanes / Q000737:chemistry* / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
D003503:Cyclobutanes