446861-48-9Relevant articles and documents
Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship
Christensen, Mette K.,Erichsen, Kamille D.,Olesen, Uffe H.,Tj?rnelund, Jette,Fristrup, Peter,Thougaard, Annemette,Nielsen, S?ren Jensby,Sehested, Maxwell,Jensen, Peter B.,Loza, Einars,Kalvinsh, Ivars,Garten, Antje,Kiess, Wieland,Bj?rkling, Fredrik
supporting information, p. 9071 - 9088 (2014/01/06)
Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm3), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
Derivatives of squaric acid with anti-proliferative activity
-
Page/Page column 20, (2008/12/08)
The present invention provides derivatives of squaric acid, in particular derivatives of 3,4-diamino-cyclobut-3-ene-1,2-dione and tautomers and isomers thereof, as a single stereoisomer or a mixture of stereoisomers, or as a pharmaceutically acceptable sa
Derivatives of squaric acid with anti-proliferative activity
-
Page/Page column 26, (2008/06/13)
The present invention provides derivatives of squaric acid, in particular derivatives of 3,4-diamino-cyclobut-3-ene-1,2-dione and tautomers thereof, as a single stereoisomer or a mixture of stereoisomers, or as a pharmaceutically acceptable salt thereof.
Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 1. N-cyanoguanidine bioisosteres possessing in vive bladder selectivity
Butera, John A.,Antane, Madelene M.,Antane, Schuyler A.,Argentieri, Thomas M.,Freeden, Chris,Graceffa, Russell F.,Hirth, Bradford H.,Jenkins, Douglas,Lennox, Joseph R.,Matelan, Edward,Norton, N. Wesley,Quagliato, Dominick,Sheldon, Jeffrey H.,Spinelli, Walter,Warga, Dawn,Wojdan, Alexandra,Woods, Morgan
, p. 1187 - 1202 (2007/10/03)
A structurally novel series of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel openers is described. As part of our efforts directed toward identifying novel, bladder-selective potassium channel openers (KCOs) targeted for urge urinary incontinence (UUI), we found that bioisosteric replacement of the N-cyanoguanidine moiety of pinacidil (1, Figure 1) with a diaminocyclobutenedione template afforded squaric acid analogue 2, the prototype of a novel series of K(ATP) channel openers with unique selectivity for bladder smooth muscle in vive. Further modification of the heterocyclic ring to give substituted aryl derivatives (3) afforded potent KCOs that possessed the desired detrusor selectivity when administered orally. The effects of these potassium channel agonists on bladder contractile function was studied in vitro using isolated rat detrusor strips. Potent relaxants were evaluated in vive in a rat model of bladder instability. Lead compounds were evaluated concomitantly in normotensive rats for their effects on mean arterial blood pressure (MAP) and heart rate as a measure of in vive bladder selectivity. (R)-4-[3,4-Dioxo-2-(1,2,2-trimethyl- propylamino)-cyclobut-1-enyαmino]-3-ethyl-benzonitrile (79) met our potency and selectivity criteria and represents an attractive development candidate for the treatment of UUI. Electrophysiological studies using isolated rat bladder detrusor myocytes have demonstrated that compound 79 produces significant hyperpolarization which is glyburide-reversed, thus consistent with the activation of K(ATP). The design, synthesis, structure-activity relationships (SAR), and pharmacological activity associated with this series of novel KCOs will be discussed.
Substituted N-heteroaryl and N-aryl-1,2-diaminocyclobutene-3,4-diones
-
, (2008/06/13)
The compounds of the formula: STR1 wherein: R1 and R2 are, independently, hydrogen, straight or branched chain alkyl or mono- or bi-cyclic alkyl; A is a substituted phenyl group containing one cyano substituent and one substituent se
Substituted n-aryl-1,2-diaminocyclobutene-3,4-diones
-
, (2008/06/13)
The compound of the formula (I) or a pharmaceutically acceptable salt thereof, are smooth muscle relaxants STR1
Substituted N-heteroaryl and N-aryl-1,2-diaminocyclobutene-3,4-diones
-
, (2008/06/13)
The compounds of the formula: STR1 wherein: R1 and R2 are, independently, hydrogen, straight or branched chain alkyl or mono- or bi-cyclic alkyl; A is an N-heterocycle which may be substituted by alkyl, perfluoroalkyl, alkoxy, perflu
