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Background and Purpose: The cannabinoid CB 1 receptor has a well-established role in appetite regulation. Drugs antagonizing central CB 1 receptors, most notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals but were discontinued due to psychiatric side effects. However, metabolic benefits were only partially attributable to weight loss, implying a role for peripheral receptors, and peripherally restricted CB 1 receptor antagonists have since been of interest. Herein, we describe the evaluation of the peripherally restricted potent CB 1 receptor inverse agonists TM38837 and TM39875, with acidic functionality, which were administered daily to diet-induced obese (DIO) mice for 5 weeks at doses for which CNS-mediated effects were minimal., Experimental Approach: Compounds were tested in dose-response in acute studies to compare efficacy (gastric transport) and extent of CNS exposure (hypothermia and satiety sequence) to demonstrate peripheral restriction and select doses for the subsequent chronic DIO study., Key Results: TM38837 but not TM39875 produced considerable (26%) weight loss, linked to a sustained reduction in food intake, together with improvements in plasma markers of inflammation and glucose homeostasis. Pharmacokinetic analysis indicated high plasma and low brain levels for both compounds with high liver levels for TM38837 (but not TM39875) due to hepatic uptake., Conclusion and Implications: Weight loss and metabolic benefits of TM38837 are likely not CNS-mediated but could be linked to enhanced liver exposure, which implicates intracellular CB 1 receptors in hepatocytes as a possible driver of obesity and co-morbidities., (© 2024 British Pharmacological Society.)