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.
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Authors | J O Johnston, C L Wright, G W Holbert, H D Benson |
Journal | Journal of enzyme inhibition
(J Enzyme Inhib)
Vol. 4
Issue 2
Pg. 137-42
( 1990)
ISSN: 8755-5093 [Print] Switzerland |
PMID | 2098520
(Publication Type: Journal Article)
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Chemical References |
- Aromatase Inhibitors
- Indicators and Reagents
- Androstenedione
- Pargyline
- Aromatase
- plomestane
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Topics |
- Androstenedione
(analogs & derivatives, chemical synthesis, metabolism, pharmacology)
- Aromatase
(metabolism)
- Aromatase Inhibitors
- Biotransformation
- Female
- Humans
- Indicators and Reagents
- Kinetics
- Microsomes
(enzymology)
- Pargyline
(analogs & derivatives, metabolism, pharmacology)
- Placenta
(enzymology)
- Structure-Activity Relationship
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