**1. Introduction**

HSG4112 is a new drug candidate which has been developed as a treatment for obesity. Its chemical structure is derived from glabridin. Glabridin is an isoflavane, which is found in *Glycyrrhiza glabra* extract [1–3]. It is known to have whitening activity by suppressing the activity of tyrosinase during the synthesis of melanin and to help alleviate gastroenteric disorders. Recently, it was confirmed that glabridin is effective in metabolic syndromes, including hyperlipidemia, fatty liver, impaired glucose metabolism, diabetes, and obesity and has anti-inflammatory actions, anticancer actions, and the like [4]. However, in spite of useful medicinal efficacy, glabridin is easily broken down by sunlight, moisture, acidity, basicity, oxygen, heat, and the like due to low chemical stability, so it is very difficult to develop a product actually utilizing glabridin [4]. For these reasons, we synthesized a new pyranochromenylphenol derivative, HSG4112, by modifying the structure of glabridin. HSG4112 is stable under various physical conditions, while maintaining or improving its medicinal efficacy [4]. HSG4112 is a racemic compound with a chiral carbon. Thus, glabridin has the structure of R-enantiomer whereas HSG4112 is a mixture of S and R enantiomers (Figure 1).

**Figure 1.** Chemical structures of (**A**) HSG4112 and (**B**) glabridin.

In many cases with chiral drugs, one of the two enantiomers is active and the other is either non-active or even harmful [5–7]. This is because the interaction between a drug molecule and its target is dependent on its three-dimensional environment. The most famous example is thalidomide, which was sold in the 1950s; the drug was introduced as a racemic mixture for use as a sedative but was later withdrawn from the market following the occurrence of birth defects in the children of mothers who took it to treat morning sickness. It was later found that the inactive enantiomer was the cause of the teratogenicity. This disaster was a driving force behind the requirement to strictly test drugs before making them available to the public [8]. In particular, for racemate candidates, both enantiomers should be studied separately as early as possible to assess the relevance of stereoisomerism to effects and fate. Accordingly, a pharmacokinetic evaluation should be provided for each enantiomer [9,10].

In this study, the stereoselective pharmacokinetics of HSG4112 were investigated in rats and beagle dogs. In addition, the metabolic stability was investigated in liver and intestinal microsomes from five different species (rat, mouse, dog, monkey, and human) to evaluate the role of metabolism in the species differences in its stereoselective pharmacokinetic behavior.
