Carcinogenicity Assessment of Daprodustat (GSK1278863), a Hypoxia-Inducible Factor (HIF)-Prolyl Hydroxylase Inhibitor.

Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor in development for treatment of anemia of chronic kidney disease. Daprodustat's biological activity simulates components of the natural response to hypoxia; inhibition of PHDs results in HIF stabilization and modulation of HIF-controlled gene products, including erythropoietin. The carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were administered. The mouse study also included evaluation of daprodustat's 3 major circulating human metabolites. There were no neoplastic findings that were considered treatment related in either study. Exaggerated pharmacology resulted in significantly increased red cell mass and subsequent multiorgan congestion and secondary non-neoplastic effects in both species, similar to those observed in chronic toxicity studies. In rats, these included aortic thrombosis and an exacerbation of spontaneous rodent cardiomyopathy, which contributed to a statistically significant decrease in survival in high-dose males (group terminated in week 94). Survival was not impacted in mice at any dose. Systemic exposures (area under the plasma concentration-time curve) to daprodustat at the high doses in rats and mice exceed predicted maximal human clinical exposure by ≥143-fold. These results suggest that daprodustat and metabolites do not pose a carcinogenic risk at clinical doses.

Identification of a pyrimidinetrione derivative as the potent DprE1 inhibitor by structure-based virtual ligand screening.

Despite the increasing need of new antituberculosis drugs, the number of agents approved for the market has fallen to an all-time low. In response to the emerging drug resistance followed, structurally unique chemical entities will be highlighted. decaprenylphosphoryl-ß-d-ribose oxidase (DprE1) participating in the biosynthesis of mycobacterium cell wall is a highly vulnerable and validated antituberculosis target. On the basis of it, a systematic strategy was applied to identify a high-quality lead compound (compound 50) that inhibits the essential enzyme DprE1, thus blocking the synthesis of the mycobacterial cell wall to kill M. tuberculosis in vitro and in vivo. Correspondingly, the rational design and synthetic strategy for compound 50 was reported. Notably, the compound 50 has been confirmed to be no toxicity. Altogether, our data suggest the compound 50 targeting DprE1 is a promising candidate for the tuberculosis (TB) therapy.

Synthesis and anticonvulsant activity of some potential thiazolidinonyl 2-oxo/thiobarbituric acids.

A series of 5-[(N-substituted benzylidenylimino)amino]-2-oxo/thiobarbituric acids (3a-3h) have been synthesized by the condensation of 5-hydrazino-2-oxo/thiobarbituric acids (2a-2b) with various aromatic aldehydes. Cycloaddition of thioglycolic acid to 3a-3h, yielded 5-[(2'-substituted phenyl-4'-oxothiazolidin-3'-yl)amino]-2-oxo/thiobarbituric acids (4a-4h). All these compounds were screened, in vivo, for their anticonvulsant activity and acute toxicity studies. Compounds 4f and 4g were found to be most potent compounds of this series and were compared with the reference drugs, phenytoin sodium, lamotrigine and sodium valproate. The structures of these compounds have been established by IR, 1H NMR and mass spectroscopic data.

Alcohol intoxication results in rapid loss in free magnesium in brain and disturbances in brain bioenergetics: relation to cerebrovasospasm, alcohol-induced strokes, and barbiturate anesthesia-induced deaths.

In vivo 31P-nuclear magnetic resonance (31P-NMR) spectroscopy and ion-selective electrode measurements were undertaken to determine if administration of acute doses of alcohol (ALC, 0.2-6.6 g/kg), and lethal doses of barbiturate anesthesia, exert any influence on: (1) brain cellular bioenergetics, intracellular free Mg ([Mg2+]i) and intracellular pH (pHi), and (2) serum levels of ionized Mg (IMg2+), ionized calcium (ICa2+) and K+. Approximately 20-30 min after intraperitoneal administration of ALC to anesthetized rats, brain phosphocreatine (PCr)/ATP and PCr/inorganic phosphate (P(i)) ratios dropped from 2.5 to 1.7 and from 6.6 to 2.2, respectively, P(i) rose 20-200% (depending upon ALC dose), and free ADP and creatine rose significantly. ALC induced rapid decreases in the cytosolic phosphorylation potential (CPP) and free energy of ATP hydrolysis (-delta G/delta E). Following ALC administration, brain [Mg2+]i dropped rapidly (within 4-30 min) and significantly; the greater the dose of ALC, the greater the loss in brain [Mg2+]. Correlations were found between [Mg2+]i, PCr/ATP, CPP and delta G/delta E after ALC but not in control brains. Rats that exhibited ALC-induced strokes and death (unlike barbiturate death) exhibited huge elevations in [Mg2+]i. Although ALC administration does not alter brain pHi at least (up to 70 min), ALC- and barbiturate-induced death produces rapid brain intracellular acidosis. Concomitant with ALC-induced alterations in [Mg2+]i and brain cellular bioenergetics, we noted that ALC administration results in rapid elevations in serum IMg2+ and K+ but not ICa2+. These results suggest that ALC administration and heavy or binge-drinking of ALC (1) can result in rapid alterations in brain bioenergetics, [Mg2+]i and pHi, and (2) result in rapid elevations in serum IMg2+ and K+ in rats. In addition, ALC- and barbiturate-induced deaths do not appear to produce identical alterations in brain bioenergetics and [Mg2+]i, and lastly binge or heavy drinking of ALC may result in stroke-like events and sudden death via rapid alterations in brain cellular bioenergetics.