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6-Azasteroids: structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase.

Publication ,  Journal Article
Frye, SV; Haffner, CD; Maloney, PR; Mook, RA; Dorsey, GF; Hiner, RN; Cribbs, CM; Wheeler, TN; Ray, JA; Andrews, RC
Published in: J Med Chem
July 22, 1994

6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.

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Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

July 22, 1994

Volume

37

Issue

15

Start / End Page

2352 / 2360

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Steroid Isomerases
  • Rats, Sprague-Dawley
  • Rats
  • Medicinal & Biomolecular Chemistry
  • Isoenzymes
  • Humans
  • Dogs
  • Azasteroids
  • Animals
 

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Frye, S. V., Haffner, C. D., Maloney, P. R., Mook, R. A., Dorsey, G. F., Hiner, R. N., … Andrews, R. C. (1994). 6-Azasteroids: structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase. J Med Chem, 37(15), 2352–2360. https://doi.org/10.1021/jm00041a014
Frye, S. V., C. D. Haffner, P. R. Maloney, R. A. Mook, G. F. Dorsey, R. N. Hiner, C. M. Cribbs, T. N. Wheeler, J. A. Ray, and R. C. Andrews. “6-Azasteroids: structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase.J Med Chem 37, no. 15 (July 22, 1994): 2352–60. https://doi.org/10.1021/jm00041a014.
Frye SV, Haffner CD, Maloney PR, Mook RA, Dorsey GF, Hiner RN, Cribbs CM, Wheeler TN, Ray JA, Andrews RC. 6-Azasteroids: structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase. J Med Chem. 1994 Jul 22;37(15):2352–2360.
Journal cover image

Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

July 22, 1994

Volume

37

Issue

15

Start / End Page

2352 / 2360

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Steroid Isomerases
  • Rats, Sprague-Dawley
  • Rats
  • Medicinal & Biomolecular Chemistry
  • Isoenzymes
  • Humans
  • Dogs
  • Azasteroids
  • Animals