Synthesis and Aromatase Inhibition of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones

J Med Chem. 1992 Jun 12;35(12):2210-4. doi: 10.1021/jm00090a010.

Abstract

The synthesis of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones is described [cyclopentyl (1), cyclohexyl (2)]. The enantiomers of 2 were separated either by using HPLC on optically active sorbent or by crystallization of the brucine salt of the phthalamic acid of 2. The absolute configuration of the (+)- and (-)-enantiomers of 2 were assigned as S and R, respectively, by comparing the CD spectra to those of the enantiomers of aminoglutethimide (AG, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The compounds were tested in vitro for inhibition of human placental aromatase, the cytochrome P450-dependent enzyme which is responsible for the conversion of androgens to estrogens. Compounds 1 and 2 inhibited aromatase by 50% at 1.2 and 0.3 microM, respectively (IC50 AG = 37 microM). According to the findings with AG, the (+)-enantiomer of 2 was responsible for the inhibitory activity, being a 240-fold more potent aromatase inhibitor in vitro than racemic AG. On the other hand, (+)-2 displayed a strongly reduced inhibition of desmolase (cholesterol side-chain cleavage enzyme) compared to AG (relative activity = 0.3). Thus (+)-2 is of interest as a potential drug for the treatment of estrogen-dependent diseases, e.g. mammary tumors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoglutethimide / pharmacology
  • Aromatase Inhibitors*
  • Cholesterol Side-Chain Cleavage Enzyme / antagonists & inhibitors
  • Chromatography, High Pressure Liquid
  • Circular Dichroism
  • Crystallization
  • Female
  • Humans
  • Molecular Conformation
  • Piperidones / chemical synthesis*
  • Piperidones / chemistry
  • Piperidones / pharmacology
  • Placenta / enzymology
  • Stereoisomerism

Substances

  • Aromatase Inhibitors
  • Piperidones
  • Aminoglutethimide
  • 3-(4-aminophenyl)-3-cyclohexylpiperidine-2,6-dione
  • Cholesterol Side-Chain Cleavage Enzyme