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The design of a new series of β3-Adrenergic receptor (β3-AdrR) antagonists is described. The use of a spiro building block in the core of the molecule provided novel compounds with reduced aromaticity and antagonist activity at the human β3-AdrR. A shortening of this core and exploration of a series of sulfonamide derivatives produced compounds with good selectivity over β1-AdrR and β2-AdrR. Alternative substitutions on the terminal aromatic rings produced compounds with further improvements in selectivity, particularly with respect to β2-AdrR. Finally, the incorporation of heteroatoms into the fused aromatic ring provided significant improvements in solubility. One compound from the series was shown to antagonize the effect of an exogenously administered β3-AdrR agonist on left ventricular pressure in the rat, making this a series of high interest for further Lead Optimization. more...