Bexlosteride

Despite the clinical evidence that androgens stimulate sebaceous lipids, androgens in vitro have shown no similar effects. This contradiction led to the assumption that cofactors may be required for lipid regulation and peroxisome proliferator-activated receptor (PPAR) ligands were suggested to be adequate candidates.

The influence of testosterone and linoleic acid, a PPAR ligand, as single agents and in combination with of LY191704, a 5alpha-reductase type I inhibitor, was examined on 5alpha-dihydrotestosterone (5alpha-DHT) synthesis and lipid content in human SZ95 sebocytes.

Cell proliferation and viability were measured by the 4-methylumbelliferyl heptanoate fluorescence assay and by the Boehringer Lactate Dehydrogenase Assay kit, respectively. 5alpha-DHT enzyme-linked immunosorbent assay was used for the detection of 5alpha-DHT synthesis in cell supernatants after treatment, whereas lipid production was documented by means of the Nile red lipid microassay and fluorescence microscopy.

Testosterone promoted 5alpha-DHT synthesis (P < 0.001), whereas linoleic acid increased sebaceous lipids (P < 0.001). The combination of testosterone and linoleic acid exhibited a synergistic effect on the synthesis of 5alpha-DHT (P < 0.01 vs. testosterone) and sebaceous lipids (P < 0.01 vs. linoleic acid). Furthermore, LY191704 reduced 5alpha-DHT and sebaceous lipid levels (P < 0.01 and P < 0.001 in comparison with testosterone/linoleic acid, respectively). Cell proliferation and viability remained unchanged under treatment with all compounds tested.

These data suggest a catalytic effect of PPAR ligands on cellular testosterone activation by 5alpha-reduction and the importance of the latter for the regulation of sebaceous lipids.

In today's drug discovery process, the very early consideration of ADME properties is aimed at a reduction of drug candidate drop out rate in later development stages. Apart from in vitro testing, in silico methods are evaluated as complementary screening tools for compounds with unfavorable ADME attributes. Especially members of the cytochrome P450 (P450) enzyme superfamily-- e.g. P450 1A2, P450 2C9, P450 2C19, P450 2D6, and P450 3A4-- contribute to xenobiotic metabolism, and compound interaction with one of these enzymes is therefore critically evaluated. Pharmacophore models are widely used to identify common features amongst ligands for any target. In this study, both structure-based and ligand-based models for prominent drug-metabolizing members of the P450 family were generated employing the software packages LigandScout and Catalyst. Essential chemical ligand features for substrate and inhibitor activity for all five P450 enzymes investigated were determined and analyzed. Finally, a collection of 11 pharmacophores for substrates and inhibitors was evaluated as an in silico P450 profiling tool that could be used for early ADME estimation of new chemical entities.