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Synthesis and in vitro evaluation of 4-substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-17 beta-carboxamides as 5 alpha-reductase inhibitors and antiandrogens.

Abstract
4-Substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-17 beta-carboxamides with the hydroxy (OH) 3d, mercapto (SH) 3e, chloro (Cl) 3f, and bromo (Br) 3g substituents at the 4-position were prepared in a two-step sequence with overall yields of 21%, 27%, 41%, and 37%, respectively. Compounds 3d-g showed weak inhibitory activity on human type I 5 alpha-reductase (IC50 > or = 700 nM) while they had intermediate inhibitory activity on human type II 5 alpha-reductase at IC50S of 172, 437, 192, and 387 nM, respectively. In androgen-sensitive Shionogi cells, the inhibition of dihydrotestosterone (DHT) stimulatory action on the proliferation of the androgen-sensitive cancer cells by all four compounds was high at IC50S of 170-279 nM compared with 117 nM for hydroxyflutamide. The present data show compounds having both moderate inhibition of human type II 5 alpha-reductase activity and relatively potent antiandrogenic action, two beneficial characteristics in the therapy of androgenic-sensitive diseases.
AuthorsX Li, S M Singh, J Côté, S Laplante, R Veilleux, F Labrie
JournalJournal of medicinal chemistry (J Med Chem) Vol. 38 Issue 9 Pg. 1456-61 (Apr 28 1995) ISSN: 0022-2623 [Print] United States
PMID7739004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 5-alpha Reductase Inhibitors
  • Androgen Antagonists
  • Androstenes
Topics
  • 5-alpha Reductase Inhibitors
  • Androgen Antagonists (chemical synthesis, pharmacology)
  • Androstenes (chemical synthesis, pharmacology)
  • Animals
  • Cell Division (drug effects)
  • Humans
  • Mice
  • Tumor Cells, Cultured

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