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 presente d as part of our program toward designing new, bladder-selective compounds for the treatment of urge urinary incontinence (UUI). We have found that th e in vitro potency of (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cycl obut-1-enylamino]3-ethyl-benzonitrile 1 in the relaxation of precontracted rat detrusor strips can also be obtained with cyanobenzylamine derivative 4 (IC50 = 0.29 mu M) (Figure 3). Addition of a 2-Cl substituted benzylamine moiety and changing the alkylamino substituent of 4 to a t-Bu amine gives 3 1 (IC50 = 0.14 mu M)-a compound with similar in vitro potency as 4 as well as relaxant activity on bladder smooth muscle in vivo when administered ora lly (31, ED50 = 3 mg/kg) in a rodent model of bladder instability. Further modifications, particularly the replacement of the t-Bu amino substituent w ith a tert-amylamine, gave a similarly active compound 60 (IC50 = 0.10 mu M ) which shows excellent in vivo efficacy (ED50 = 0.6 mg/kg). Moreover, 60, 3-(2,4-dichloro-6-methyl-benzylamino)-4- 1,1-dimethylpropylamino)-cyclobut- 3-ene-1,2-dione (WAY-151616), shows excellent tissue selectivity for bladde r K channels over arterial tissue (60, MAP ED20 = 100 mg/kg; selectivity: M AP ED20/ bladder ED50 = 166). Other manipulations of the benzylamino cyclob utenediones, acylation of the benzylamine, conversion of the benzylamine su bstituent to a benzamide, homologation of the benzylamine to a phenethylami ne, and incorporation of a methyl group at the benzyl carbon, all led to su bstantial loss of in vitro activity, although some in vivo activity was mai ntained in the acylated analogues. Compound 60 represents an attractive can didate for development in the treatment of UUI.