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A-ring bridged steroids as potent inhibitors of aromatase. 1993

N P Peet, and J O Johnston, and J P Burkhart, and C L Wright
Marion Merrell Dow Research Institute, Cincinnati, OH 45215.

The design and syntheses of androstenedione derivatives with bridges spanning the 2,19-, 3,19-, 4,19- and 6, 19-positions are described. 2,19-Bridged compounds bearing hydroxyl groups on the two-carbon bridge (3a and 3b) were designed as stable carbon analogs of potential lactol intermediates in the enzymatic conversion of androgens to estrogens. Compounds 3a and 3b are competitive inhibitors of aromatase. Pyran 25 is a potent, time-dependent inhibitor of aromatase with partial NADPH dependence. These data suggest a mechanism of inhibition for 25 which involves both tight-binding competitive and mechanism-based components, with the former predominating. The sulfur, amino, and all carbon analogs of pyran 25 were prepared. Thiopyran 36, piperidine 42 and the all-carbon analog 47 are also time-dependent inhibitors of aromatase. Compound 47 is the most potent inhibitor and its time-dependent inhibition is not NADPH dependent. The kinetics of piperidine 42 suggest uncompetitive inhibition.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer
D013256 Steroids A group of polycyclic compounds closely related biochemically to TERPENES. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (STEROLS), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. (From Hawley's Condensed Chemical Dictionary, 11th ed) Steroid,Catatoxic Steroids,Steroids, Catatoxic
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D047072 Aromatase Inhibitors Compounds that inhibit AROMATASE in order to reduce production of estrogenic steroid hormones. Aromatase Inhibitor,Inhibitor, Aromatase,Inhibitors, Aromatase

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