STRUCTURE-ACTIVITY-RELATIONSHIPS OF A NEW FAMILY OF STEROIDAL AROMATASE INHIBITOR .1. SYNTHESIS AND EVALUATION OF A SERIES OF ANALOGS RELATED TO 19-[(METHYLTHIO)METHYL]ANDROSTENEDIONE (RU54115)

During the course of a study aimed at the search for new potent aromat ase inhibitors, several new androstenedione analogs were synthesized a nd evaluated. This study led to the discovery of ethylthio)methyl]andr osta-4,9(11)-diene-3,17-dione (7; RU54115) already described by our la boratory. The object of the present series of papers is to disclose th e 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 var ied, the length of the chain and its rigidity and branching, as well a s the nature of the heteroatom itself and its substitution. The intera ction of these new compounds with human placental aromatase in competi tion with the substrate androstenedione was studied by difference visi ble spectroscopy. The in vivo aromatase-inhibiting activities were eva luated by measuring the estradiol lowering after oral administration o f the compounds to PMSG-primed female rats.