During the course of a study aimed at the search for new potent aromatase inhibitors, several new androstenedione analogs were synthesized and evaluated. This study led to the discovery of 19-[(methylthio)methyl]androsta-4,9(11)-diene-3,17-dione (7; RU54115) already described by our laboratory. The object of the present series of papers is to disclose the result of the structure-activity relationship studies that gave rise to this compound. This first part deals mainly with the substitution in the 19-position of the steroid nucleus. Several parameters were varied, the length of the chain and its rigidity and branching, as well as the nature of the heteroatom itself and its substitution. The interaction of these new compounds with human placental aromatase in competition with the substrate androstenedione was studied by difference visible spectroscopy. The in vivo aromatase-inhibiting activities were evaluated by measuring the estradiol lowering after oral administration of the compounds to PMSG-primed female rats.