Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 2. Selective and potent benzylamino cyclobutenediones.
A novel series of benzylamine, potassium channel openers (KCOs) is presented as part of our program toward designing new, bladder-selective compounds for the treatment of urge urinary incontinence (UUI). We have found that the in vitro potency of (R)-4-[3,4-dioxo-2-(1,2, 2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzo nitrile 1 in the relaxation of precontracted rat detrusor strips can also be obtained with cyanobenzylamine derivative 4 (IC(50) = 0.29 microM) (Figure 3). Addition of a 2-Cl substituted benzylamine moiety and changing the alkylamino substituent of 4 to a t-Bu amine gives 31 (IC(50) = 0.14 microM)-a compound with similar in vitro potency as 4 as well as relaxant activity on bladder smooth muscle in vivo when administered orally (31, ED(50) = 3 mg/kg) in a rodent model of bladder instability. Further modifications, particularly the replacement of the t-Bu amino substituent with a tert-amylamine, gave a similarly active compound 60 (IC(50) = 0.10 microM) which shows excellent in vivo efficacy (ED(50) = 0.6 mg/kg). Moreover, 60, 3-(2,4-dichloro-6-methyl-benzylamino)-4-(1, 1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (WAY-151616), shows excellent tissue selectivity for bladder K channels over arterial tissue (60, MAP ED(20) = 100 mg/kg; selectivity: MAP ED(20)/bladder ED(50) = 166). Other manipulations of the benzylamino cyclobutenediones, acylation of the benzylamine, conversion of the benzylamine substituent to a benzamide, homologation of the benzylamine to a phenethylamine, and incorporation of a methyl group at the benzyl carbon, all led to substantial loss of in vitro activity, although some in vivo activity was maintained in the acylated analogues. Compound 60 represents an attractive candidate for development in the treatment of UUI.
Gilbert
A M
AM
Chemical Sciences, Wyeth-Ayerst Research, Pearl River, New York 10965-1299, USA. gilbera@war.wyeth.com
Antane
M M
MM
Argentieri
T M
TM
Butera
J A
JA
Francisco
G D
GD
Freeden
C
C
Gundersen
E G
EG
Graceffa
R F
RF
Herbst
D
D
Hirth
B H
BH
Lennox
J R
JR
McFarlane
G
G
Norton
N W
NW
Quagliato
D
D
Sheldon
J H
JH
Warga
D
D
Wojdan
A
A
Woods
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000819:agonists*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology; D014549:Urinary Incontinence / Q000188:drug therapy
D001596:Benzylamines; D003503:Cyclobutanes; D015221:Potassium Channels; C406345:WAY 151616; D011189:Potassium Chloride; D000255:Adenosine Triphosphate