80047-24-1Relevant articles and documents
Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition
Fearon, Daren,Westwood, Isaac M.,van Montfort, Rob L.M.,Bayliss, Richard,Jones, Keith,Bavetsias, Vassilios
supporting information, p. 3021 - 3029 (2018/05/25)
Screening a 3-aminopyridin-2-one based fragment library against a 26-kinase panel representative of the human kinome identified 3-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (2) and 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one (3) as ligand efficient inhibitors of the mitotic kinase Monopolar Spindle 1 (MPS1) and the Aurora kinase family. These kinases are well recognised as attractive targets for therapeutic intervention for treating cancer. Elucidation of the binding mode of these fragments and their analogues has been carried out by X-ray crystallography. Structural studies have identified key interactions with a conserved lysine residue and have highlighted potential regions of MPS1 which could be targeted to improve activity and selectivity.
Bipyridine Cardiotonics: The Three-Dimensional Structures of Amrinone and Milrinone
Robertson, David W.,Beedle, E. E.,Swartzendruber, John K.,Jones, Noel D.,Elzey, T. K.,et al.
, p. 635 - 640 (2007/10/02)
The cardiotonic drug milrinone (1,6-dihydro-2-methyl-6-oxo--5-carbonitrile) is superior to its analogue amrinone (5-amino--6(1H)-one) by virtue of its greater potency and reduced side effect profile.We confirmed initial reports on the potencies of milrinone and amrinone and found that after intravenous administration to phenobarbital anesthetized dogs, the drug had cumulative inotropic ED50's of 37 and 1891 μg/kg, respectively; relative effects on heart rate and blood pressure were comparable.There are two structural differences between amrinone and milrinone: (1) milrinone has a pyridone 2-methyl substituent and (2) the pyridone 5-amino substituent of amrinone is replaced with a nitrile in milrinone.We confirmed structure-activity studies that indicated that the 2-methyl substituent appears to be primarily responsible for the dramatic difference in the potencies of amrinone and milrinone.A plausible explanation for the effect of the methyl substituent is an altered molecular topology resulting from its steric interaction with the 3',5'-hydrogen atoms.Consequently, we probed the three-dimensional structures of these two compounds by X-ray crystallography.The dihedral angle between the planes formed by the two aromatic rings of amrinone was 1.3 deg.In marked contrast, the corresponding angle for milrinone was 52.2 deg.Moreover, 1H NMR studies revealed conformational differences in solution.Whereas the 2-methyl substituent undoubtedly produces some electronic and hydrophobic perturbations in the bipyridine cardiotonic series, the most significant effect, from a global viewpoint, is the altered molecular topology.
Process for preparing 5 pyridyl pyridine-2 (1H)-ones
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, (2008/06/13)
5-Pyridinyl-6-R2 -3-R1 -2(1H)-pyridinones (I), where R2 is hydrogen or lower alkyl and R1 is a cyano, a carbamoyl or an amino group are prepared: by reaction of 1-R2 -1-oxo-2-pyridinyl-3-dialkylaminopropane (II) with malonamide under solid-liquid or liquid-liquid phase transfer catalysis conditions to obtain 1,2-dihydro-2-oxo-6-R2 -5-pyridinylnicotinamide (IV), or by reaction of II with cyanoacetamide under solid-liquid or liquid-liquid phase transfer catalysis conditions to obtain 1,2-dihydro-2-oxo-6-R2 -5-pyridinylnicotinonitrile (III) and partially hydrolizing III to yield IV; finally the carbamoyl group of IV is converted to amino and 1,2-dihydro-2-oxo-6-R2 -5-pyridinyl-3-aminopyridin-2-one are obtained.
