78504-61-7

A synthetic procedure for producing 14C-labelled milr inone is described. The synthesis was achieved in two steps from 1-(4-pyridyl)propan-2- one utilising [2-14C] cyanoacetamide as the source of the radiolabel. The overall chemical yield was 46% and the radiochemical yield 35%.

The invention discloses a preparation method of a compound 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one, and belongs to the technical field of medicine synthesis. The method comprises the following steps: reacting a solid compound intermediate I with N, N-dimethylformamide dimethyl acetal to obtain 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one; the invention also provides a method for preparing milrinone by using 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one, and the method is simple and convenient to operate, high in safety, high in yield and suitable for industrial large-scale production. The appearance and purity of the obtained milrinone finished product reach the standard.

A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability.

Glucocorticoids are one of the most utilized and effective therapies in treating T-cell acute lymphoblastic leukemia. However, patients often develop resistance to glucocorticoids, rendering these therapies ineffective. We screened 9517 compounds, selected for their lead-like properties, chosen from among 3372615 compounds, against a dexamethasone-resistant T-ALL cell line to identify small molecules that reverse glucocorticoid resistance. We synthesized analogues of the most effective compound, termed J9, from the screen in order to define the scaffolds structure-activity relationship. Active compounds restored sensitivity to glucocorticoids through upregulation of the glucocorticoid receptor. This compound and mechanism may provide a strategy for overcoming glucocorticoid resistance in patients with T-ALL.

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.