202521-88-8Relevant articles and documents
Hit to Lead optimization of a novel class of squarate-containing polo-like kinases inhibitors
Zhang, Qingwei,Xia, Zhiren,Mitten, Michael J.,Lasko, Loren M.,Klinghofer, Vered,Bouska, Jennifer,Johnson, Eric F.,Penning, Thomas D.,Luo, Yan,Giranda, Vincent L.,Shoemaker, Alexander R.,Stewart, Kent D.,Djuric, Stevan W.,Vasudevan, Anil
supporting information, p. 7615 - 7622 (2013/02/23)
A high throughput screening (HTS) hit, 1 (Plk1 Ki = 2.2 μM) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor-acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 Ki = 5 nM; EC50 = 1.05 μM), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity.
Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 2. Selective and potent benzylamino cyclobutenediones
Gilbert, Adam M.,Antane, Madelene M.,Argentieri, Thomas M.,Butera, John A.,Francisco, Gerardo D.,Freeden, Chris,Gundersen, Eric G.,Graceffa, Russell F.,Herbst, David,Hirth, Bradford H.,Lennox, Joseph R.,McFarlane, Geraldine,Norton, N. Wesley,Quagliato, Dominick,Sheldon, Jeffrey H.,Warga, Dawn,Wojdan, Alexandra,Woods, Morgan
, p. 1203 - 1214 (2007/10/03)
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-benzonitrile 1 in the relaxation of precontracted rat detrusor strips can also be obtained with cyanobenzylamine derivative 4 (IC50 = 0.29 μM) (Figure 3). Addition of a 2-Cl substituted benzylamine moiety and changing the alkylamino substituent of 4 to a t-Bu amine gives 31 (IC50 = 0.14 μM) - a compound with similar in vitro potency as 4 as well as relaxant activity on bladder smooth muscle in vivo when administered orally (31, ED50 = 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 (IC50 = 0.10 μM) 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 bladder K channels over arterial tissue (60, MAP ED20 = 100 mg/kg; selectivity: MAP ED20/bladder ED50 = 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.
