title: Structure-activity relationships of a new family of steroidal aromatase inhibitors. 1. Synthesis and evaluation of a series of analogs related to 19-[(methylthio)methyl]androstenedione (RU54115).
abstract: 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.
authors.affiliation: Centre de Recherche de Roussel Uclaf, Romainville, France.
authors.forename: D
authors.initials: D
authors.lastname: Lesuisse
authors.forename: J F
authors.initials: JF
authors.lastname: Gourvest
authors.forename: O
authors.initials: O
authors.lastname: Benslimane
authors.forename: F
authors.initials: F
authors.lastname: Canu
authors.forename: C
authors.initials: C
authors.lastname: Delaisi
authors.forename: B
authors.initials: B
authors.lastname: Doucet
authors.forename: C
authors.initials: C
authors.lastname: Hartmann
authors.forename: J M
authors.initials: JM
authors.lastname: Lefrançois
authors.forename: B
authors.initials: B
authors.lastname: Tric
authors.forename: D
authors.initials: D
authors.lastname: Mansuy
authors.forename: D
authors.initials: D
authors.lastname: Philibert
authors.forename: G
authors.initials: G
authors.lastname: Teutsch
mesh_terms: D000818:Animals; D001141:Aromatase / Q000302:isolation & purification; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004963:Estrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000201:enzymology; D010920:Placenta / Q000201:enzymology; D051381:Rats; D013055:Spectrophotometry, Infrared; D013256:Steroids / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004963:Estrenes; D013256:Steroids; C074095:10-methylthioethyl estra-4,9(11)-diene 3,17-dione; D001141:Aromatase