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.
The present study was aimed to investigate the effects of MB12662, a synthetic dunnione compound, on cisplatin-induced vomiting reflexes and intestinal, renal, immune system, and hematopoietic toxicities in ferrets and mice, respectively. Male ICR mice were orally administered MB12662 (5, 10, 25 or 50 mg/kg) for 10 days, during which intraperitoneally challenged with cisplatin (3.5 mg/kg) from day 4 to 7, and sacrificed on day 10 for the pathological examination. Male ferrets were orally administered MB12662 (25, 50 or 100 mg/kg) for 7 days, subcutaneously challenged with cisplatin (5 mg/kg), and monitored for vomiting reflexes and survival of the animals. Four-day injection of cisplatin (3.5 mg/kg) to mice caused body weight loss and degeneration and atrophy of intestinal villi, reducing villi/crypt ratio to a half level of control animals. Cisplatin also induced renal and hepatic toxicities, and depletion of splenocytes and bone marrow progenitor cells. The systemic toxicities including decreased villi/crypt ratio, immune system atrophy, splenocyte depletion, and decreased cellularity in bone marrow were improved by MB12662. Cisplatin (5 mg/kg) induced retching and emetic responses of ferrets, which were remarkably attenuated by MB12662 in a dose-dependent manner. All the ferrets pretreated with MB12662 survived the challenge of cisplatin, in comparison with 40% mortality in vehicle-treated animals, and blood parameters of nephrotoxicity and hepatotoxicity were markedly recovered. It is expected that MB12662 could be a candidate for the body protection against burden, including emesis, of chemotherapeutic agents.
HGR4113 is a novel compound that was discovered by Glaceum Inc. through a Quantitative Structure-Activity Relationship (QSAR) study on Glabridin and its derivatives. HGR4113 showed competitive antihyperglycemic effects in db/db mice without any adverse event of obesity. The test consisted of a vehicle control group (db/db mice), a test group (HGR4113 150mg/kg), and two positive control groups (Metformin 300mg/kg and Pioglitazone 75mg/kg). HGR4113 was given orally once daily for 7 days for 8 consecutive weeks (qd×7×8). During the course of this study, HGR4113 exhibited a level of efficacy highly comparable to Pioglitazone, one of the oral antihyperglycemic agents available. More importantly, however, HGR4113 demonstrated weight maintenance effects similar to Metformin in db/db mice, whereas Pioglitazone caused db/db mice to develop significant signs of obesity as a critical adverse effect. In conclusion, our test results suggest HGR4113 as a safe and effective drug for T2DM along with further clinical development. Disclosure K. Kim: None. S. Yoo: Employee; Self; Glaceum. I. Jo: Employee; Self; Glaceum Incoporation. K. Lim: Employee; Self; Glaceum Inc..
HSG4112 is an Investigational New Drug (IND) discovered by Glaceum Inc. through Quantitative Structure-Activity Relationship (QSAR) study on Glabridin and its derivatives. It is currently in Phase 1 study as a treatment for obesity. In nonclinical studies, HSG4112 showed a significant body-weight reduction effect with excellent safety profiles in Diet-Induced Obesity (DIO) mice. The test consisted of a normal control group (normal diet), a vehicle control group (high fat diet), a test group (HSG4112 100mg/kg) and a pair-fed group. HSG4112 was given orally once daily for 7 days for 6 consecutive weeks (qd×7×6). After 6 weeks, the total mean weight loss was 10.2g (-26.0%) in the test group. The contribution made by reduced food intake was 38.0% and the energy expenditure effect was 62.0%. Increase of O2 consuming and CO2 generating rates, and decrease of 5’ Adenosine Monophosphate-activated Protein Kinase (AMPK) activity in hypothalamus after oral administration of HSG4112 to DIO mice were observed. Single oral dose toxicity study of HSG4112 was performed with rat and dog. The Maximum Tolerated Dose (MTD) 2,000mg/kg was observed from both rat and dog. In conclusion, in nonclinical studies, HSG4112 demonstrated sufficient efficacy and safety as an anti-obesity drug supporting further clinical development. Disclosure S. Yoo: Employee; Self; Glaceum. K. Kim: None. I. Jo: Employee; Self; Glaceum Incoporation. K. Lim: Employee; Self; Glaceum Inc..
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