Introduction

Obesity occurs when energy intake exceeds energy expenditure. Despite the simplicity of the causal equation, its pharmacological treatment requires a multifaceted approach due to the accompanying burdens of chronic inflammation, hypertension, dyslipidemia, and overall disruption of energy metabolism [1]. Currently existing FDA-approved anti-obesity drugs are specific receptor-targeted drugs that focus on the initial part of the equation: they reduce energy intake by inhibiting food intake or absorption [2,3]. Energy intake reduction is equivalent to calorie-restricted dieting and is prone to weight cycling (yo-yo effect) because it decreases muscle mass or muscle activity, leading to reduced metabolic function and energy expenditure [4]; hence, long-term weight loss is difficult to achieve [5,6]. In consideration of the accompanying hurdles in ameliorating obesity caused by excess energy intake, a promising anti-obesity drug or combination of drugs should consist of multi-functional effects leading to both reduced energy intake and enhanced energy expenditure, with potent clinical efficacy.  
Glabridin is a promising base compound in the pharmacological research of multi-functional, energy expenditure-enhancing anti-obesity drugs. A prenylated polyphenolic isoflavan, glabridin is an isolate and the key chemical and biological marker of Glycyrrhiza glabra L. (Fabaceae) roots, also commonly known as licorice [7,8]. Along with a long history of medicinal use of licorice, glabridin has been considered a prospective molecule for ameliorating metabolic diseases [9] due to its anti-oxidative, anti-inflammatory, and anti-atherogenic effects as well as its regulation of energy metabolism [10]. Previously, glabridin in HFD-induced obese mice was shown to reduce ~25% body weight, ameliorate lipid dysregulation, and activate the signaling pathway for AMP-activated protein kinase (AMPK) [11], an enzyme well-known for its critical role in energy homeostasis [12].
Glabridin itself has not been developed as a therapeutic drug because of several limitations, but its derivatives show potential. Glabridin has low physicochemical stability [13] and low bioavailability [14]; light, temperature, humidity, and pH all influence the stability of glabridin [13]. In addition, the extraction of glabridin from licorice is complicated and unlucrative because of glabridin’s low content and high decomposition rate in the preparation process [13]. Other compounds isolated from licorice root with glabridin backbone – hispaglabridin A and B and 4’-O-methylglabridin – demonstrated comparable antioxidative properties [7], and 3’’,4’’-dihydro-glabridin showed superior stability and tyrosinase inhibitory effects [15]. Recent studies report glabridin’s putative pharmacophore [10] and the efficient synthesis of racemic glabridin [16], thereby facilitating rational designs and syntheses of glabridin and its derivatives. Yet, the effects of glabridin derivatives as anti-obesity agents and their exact pharmacophore are unknown.
Here, we report the discovery and preclinical efficacy of a novel small oral molecule named HSG4112, which is a synthetic derivative and a structural analog of glabridin currently in clinical trial for obesity. We show that HSG4112, discovered through in vivo phenotypic validation of the SAR analysis and identification of the pharmacophore for weight loss effects, is a new chemical entity which presents potent preclinical efficacy with an energy expenditure-enhancing effect, and thus is a promising therapeutic drug candidate for the treatment of obesity.