Discovery and preclinical efficacy of HSG4112, a synthetic structural analog of glabridin, for the treatment of obesity

Abstract

Background HSG4112 is a clinical-stage drug candidate for the treatment of obesity. Here, we report its discovery and preclinical efficacy. Methods In high-fat diet (HFD)-induced obese male C57BL/6J mice, we tested the weight loss effect of synthetic compounds derived from a structure–activity relationship (SAR) study of glabridin, a natural compound known to reduce body weight and influence energy homeostasis. After selecting HSG4112 as our optimized compound from this discovery method, we characterized its pharmacological effects on parameters related to obesity through in vivo metabolic and biochemical measurements, histology and gene expression analysis, and indirect calorimetry. Results Through the SAR study, we identified four novel components of glabridin pertinent for its anti-obesity activity, and found that HSG4112, an optimized structural analog of glabridin, markedly supersedes glabridin in weight reduction efficacy and chemical stability. Six-week administration of HSG4112 to HFD-induced obese mice led to dose-dependent normalization of obesity-related parameters, including body weight, muscle and adipose tissue weight, adipocyte size, and serum leptin/insulin/glucose levels. The weight reduction induced by HSG4112 was partially mediated by decreased food intake and mainly mediated by increased energy expenditure, with no change in physical activity. Accordingly, the pattern of transcriptional changes was aligned with increased energy expenditure in the liver and muscles. Following significant body weight reduction, robust amelioration of histopathology and blood markers of fatty liver were also observed. Conclusions Our study demonstrates the key chemical components of glabridin pertinent to its weight loss effects and suggests HSG4112 as a promising novel drug candidate for the pharmacological treatment of obesity.

Intervertebral Disc and Adipokine Leptin—Loves Me, Loves Me Not

“…A synthetic structural analog of glabridin (HSG4112)—a polyphenolic compound extracted from licorice roots ( Glycyrrhiza glabra L. ( Fabaceae )—is promising anti-obesity drug, currently in clinical trial for obesity treatment [ 63 ]. A six-week administration of the analog caused return to normal body weight by high fat diet-induced obese male mice.…”

“…A six-week administration of the analog caused return to normal body weight by high fat diet-induced obese male mice. The treatment also led to the reduction of VAT and normalization of serum leptin, insulin, and glucose levels [ 63 ].…”

Vutiglabridin improves neurodegeneration in MPTP-induced Parkinson’s disease mice by targeting mitochondrial paraoxonase-2

“…Vutiglabridin (Vuti, HSG4112, Figure 1A) is a synthetic new chemical that is currently in human phase 2 clinical study (NCT05197556) for the treatment of obesity (25). Vutiglabridin is a derivative of glabridin (25), a natural prenylated polyphenolic isoflavan and an important constituent of licorice root (Glycyrrhiza glabra), and it is a racemic mixture of (R)-vutiglabridin and (S)-vutiglabridin. Glabridin is associated with numerous biological properties ranging from antioxidant, anti-inflammatory (26,27), neuroprotective (28)(29)(30), and anti-atherogenic effects to the regulation of energy metabolism (31).…”

“…Vutiglabridin (Vuti, HSG4112, Figure 1A ) is a synthetic new chemical that is currently in human phase 2 clinical study (NCT05197556) for the treatment of obesity ( 25 ). Vutiglabridin is a derivative of glabridin ( 25 ), a natural prenylated polyphenolic isoflavan and an important constituent of licorice root ( Glycyrrhiza glabra ), and it is a racemic mixture of (R)-vutiglabridin and (S)-vutiglabridin.…”

Enhancement of nutraceutical properties of licorice callus cultures using sample pre‐treatment strategy

“…Currently, a variety of food products derived from licorice is available worldwide such as tea, gummies, candy and bakery goods. Moreover, licorice has been reported to exert medicinal properties such as antimicrobial (Wang et al ., 2015), anti‐coronavirus (Polansky & Lori, 2020), anti‐hepatitis (Adianti et al ., 2014), anti‐asthma (Dogan et al ., 2020), anti‐obesity (Choi et al ., 2021) and anticancer (Wang et al ., 2021). Therefore, licorice is an important nutraceutical source.…”