Identification and human exposure prediction of two aldehyde oxidase-mediated metabolites of a methylquinoline-containing drug candidate.

1. Aldehyde oxidase (AO enzymes)-mediated oxidation predominantly occurs at a carbon atom adjacent to the nitrogen on aromatic azaheterocycles. In the current report, we identified that AO enzymes oxidation took place at both the C-2 and C-4 positions of the methylquinoline moiety of Compound A based on data from mass spectrometric analysis, AO enzymes "litmus" test, and comparison with authentic standards. 2. To assess the potential for inadequate coverage for these two AO enzyme-mediated metabolites in nonclinical safety studies, given concerns due to differences in AO enzymes expression between preclinical species and humans, the human circulating levels of the two AO enzyme-mediated metabolites were predicted prospectively using in vitro and in vivo models. Both formation clearance and elimination clearance of the two metabolites were predicted based on in vitro to in vivo correlation and comparison with in vivo data from rats. 3. The result showed that the 4-OH metabolite of Compound A would account for less than 3% of the total drug-related exposure in human plasma, while the exposure to the 2-oxo metabolite would be relatively high (∼70%). 4. The predicted human exposure levels for the two metabolites are in similar ranges as those observed in monkeys. These data taken together support the advancement to clinical development of Compound A.

The Link Between Self-Dehumanization and Immoral Behavior.

People perceive morality to be distinctively human, with immorality representing a lack of full humanness. In eight experiments, we examined the link between immorality and self-dehumanization, testing both (a) the causal role of immoral behavior on self-dehumanization and (b) the causal role of self-dehumanization on immoral behavior. Studies 1a to 1d showed that people feel less human after behaving immorally and that these effects were not driven by having a negative experience but were unique to experiences of immorality (Study 1d). Studies 2a to 2c showed that self-dehumanization can lead to immoral and antisocial behavior. Study 3 highlighted how self-dehumanization can sometimes produce downward spirals of immorality, demonstrating initial unethical behavior leading to self-dehumanization, which in turn promotes continued dishonesty. These results demonstrate a clear relationship between self-dehumanization and unethical behavior, and they extend previous theorizing on dehumanization.