347393-40-2Relevant academic research and scientific papers
Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease
Credille, Cy V.,Dick, Benjamin L.,Morrison, Christine N.,Stokes, Ryjul W.,Adamek, Rebecca N.,Wu, Nicholas C.,Wilson, Ian A.,Cohen, Seth M.
supporting information, p. 10206 - 10217 (2018/11/23)
Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PAN endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PAN endonuclease, a class of highly active and selective fragments was developed that displays IC50 values 50 values of ～10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors.
Synthesis of 2-amido-3-hydroxypyridin-4(1H)-ones: Novel iron chelators with enhanced pFe3+ values
Liu, Zu D.,Piyamongkol,Liu, Ding Y.,Khodr, Hicham H.,Lu, Shu L.,Hider, Robert C.
, p. 563 - 573 (2007/10/03)
The synthesis of a range of 2-amido-3-hydroxypyridin-4-ones as bidentate iron(III) chelators with potential for oral administration is described. The pKa values of the ligands together with the stability constants of their iron(III) complexes have been determined. Results indicate that the introduction of an amido substituent at the 2-position leads to an appreciable enhancement of the pFe3+ values. The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a 59Fe-ferritin loaded rat model. The optimal effect was observed with the N-methyl amido derivative 15b, which has an associated pFe3+ value of 21.7, more than two orders of magnitude higher than that of deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one) 1a (pFe3+=19.4). Dose response studies suggest that chelators with high pFe3+ values scavenge iron more effectively at lower doses when compared with simple dialkyl substituted hydroxypyridinones. Copyright
