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. 6-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.