Regulation of tissue-specific glucocorticoid action by inhibiting 11β-HSD1 activity is regarded as a potential viable treatment for metabolic and cardiovascular diseases. Our effort to find an alternative to the highly favoured adamantyl moiety found in many potent 11β-HSD1 inhibitors led to the synthesis and SAR study of a series of phenyl ethanone thiadiazole derivatives. Potent compounds were identified with IC values in the range 100-300 nM in biological evaluation on an HEK293 cell line stably transfected with the human HSD11B1 gene. These compounds are selective with no activity against human 11β-HSD2. An SAR study revealed the favoured combination of phenyl substitution and the linker system being meta-methoxy with a sulphide linker (18) or a para-trifluoromethyl with sulphoxide linker (27). Docking of 3 into a crystal structure of the enzyme shows how the substituted phenyl group of this new series might mimic the adamantane motif. Potent inhibitors 18 and 27 are new templates for further optimization.