title: Enzyme inactivation by potential metabolites of an aromatase-activated inhibitor (MDL 18,962).
abstract: MDL 18,962, 19-acetylenic androstenedione, is an enzyme-activated inhibitor of estrogen biosynthesis which is in Phase I clinical evaluations as a potential therapeutic agent for estrogen-dependent cancers. 19-Acetylenic analogs corresponding to the major metabolites of androstenedione were synthesized as potential metabolites of MDL 18,962. These compounds were 19-acetylenic testosterone, the product of 17 beta-hydroxy steroid oxidoreductase, 6 beta-hydroxy- and 6-oxo-19-acetylenic androstenedione, products of P450 steroid 6 beta-hydroxylase and alcohol dehydrogenase, respectively. All of these analogs showed time-dependent inactivation of human placental aromatase activity. The time-dependent Ki and t1/2 at infinite inhibitor concentration (tau 50) were 4.3 nM, 12.0 min for MDL 18,962; 28 nM, 7.8 min for 17-hydroxy analog; 13 nM, 37 min for 6 beta-hydroxy analog; and 167 nM, 6.1 min for the 6-oxo analog. The 19-acetylenic testosterone, a confirmed metabolite from primate studies, was 25% as efficient as MDL 18,962 for aromatase inactivation, while 6 beta-hydroxy- and 6-oxo analogs were 11% and 5%, respectively as efficient as their parent compound. These data indicate that first-pass metabolism of MDL 18,962 does not cause an obligatory loss of time-dependent inhibition of human aromatase activity.
authors.affiliation: Merrell Dow Research Institute, Cincinnati, OH 45215.
authors.forename: J O
authors.initials: JO
authors.lastname: Johnston
authors.forename: C L
authors.initials: CL
authors.lastname: Wright
authors.forename: G W
authors.initials: GW
authors.lastname: Holbert
authors.forename: H D
authors.initials: HD
authors.lastname: Benson
mesh_terms: D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001711:Biotransformation; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D010293:Pargyline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D007202:Indicators and Reagents; D000735:Androstenedione; D010293:Pargyline; D001141:Aromatase; C033071:plomestane