In exploring the structural features responsible for the inhibitory activity of aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] (1) toward the cholesterol side chain cleavage (CSCC) enzyme from bovine adrenals and the human placental aromatase enzyme, analogues have been synthesized in which the piperidine-2,6-dione ring is replaced by substituted or unsubstituted azabicyclo[3.1.0]hexane-2,4-dione rings. The unsubstituted analogue 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (9a) is a slightly more potent inhibitor of aromatase than 1 (Ki = 1.2 microM, cf. 1.8 microM for 1) but is noninhibitory toward the CSCC enzyme. The substituted analogues 1-(4-aminophenyl)-3-butyl-3-azabicyclo[3.1.0]hexane-2,4-dione (9e) and 1-(4-aminophenyl)-3-pentyl-3-azabicyclo[3.1.0]hexane-2,4-dione (9f) are approximately 100 times more potent than 1 (Ki values of 1, 9e, and 9f are 1.8, 0.015, and 0.02 microM, respectively) in inhibiting aromatase, with no significant activity toward the CSCC enzyme. Type II difference spectra were exhibited by 1, 9a, and 9f in their interaction with the aromatase enzyme (respective Ks values of 1, 9a, and 9f are 0.13, 0.08, and 0.01 microM). Modification of the para amino function by alkylation, its relocation, replacement by H, or replacement by a methyl, aldehyde, or secondary alcohol group produced analogues that were inactive toward both enzyme systems.