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Mechanism of time-dependent inhibition of 5 alpha-reductases by delta 1-4-azasteroids: toward perfection of rates of time-dependent inhibition by using ligand-binding energies.

Publication ,  Journal Article
Tian, G; Mook, RA; Moss, ML; Frye, SV
Published in: Biochemistry
October 17, 1995

Finasteride (17 beta-N-tert-butylcarbamoyl-4-aza-5 alpha-androstan-1-en-3- one) is a time-dependent, apparently irreversible inhibitor of 5 alpha-reductases, but does not fully inhibit the activity of 5 alpha-reductase in vivo. This limited efficacy has been attributed to its slow rate of inhibition against the type-1 isozyme [Tian, G. (1995) J. Pharm. Sci. (in press)]. Here the feasibility of increasing the rate of inhibition of 5 alpha-reductases by providing binding energies with the inhibitor at a site remote from the center of chemical transformation was explored. Substitution of N-(2,5-bis(trifluoromethyl)phenyl) group, which had been shown to benefit 6-azasteroids in the binding to 5 alpha-reductases [Frye, S., Haffner, C. D., Maloney, P. R., Hiner, R. N., Unwalla, R. J., Batchelor, K. W., Bramson, H. N., Stuart, J. D., Schweiker, S. L., Van Arnold, J., Bickett, D. M., Moss, M. L., Tian, G., Lee, F. W., Tippin, T. K., James, M. K., Grizzle, M. K., Long, J. E., & Croom, D. K. (1995) J. Med. Chem. 38, 2621-2627], for the N-tert-butyl substituent at C-17 of finasteride did not perturb the mechanism of inhibition but significantly increased the rate of inhibition of type-1 5 alpha-reductase. The rate of inhibition was too fast to determine accurately when the normal substrate testosterone was used in the progress curve analysis as this inhibition rate is approaching the value of kcat/Km for the enzyme reaction.

Duke Scholars

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

October 17, 1995

Volume

34

Issue

41

Start / End Page

13453 / 13459

Location

United States

Related Subject Headings

  • Time Factors
  • Thermodynamics
  • Testosterone
  • Substrate Specificity
  • Structure-Activity Relationship
  • Progesterone
  • Models, Theoretical
  • Mathematics
  • Ligands
  • Kinetics
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Journal cover image

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

October 17, 1995

Volume

34

Issue

41

Start / End Page

13453 / 13459

Location

United States

Related Subject Headings

  • Time Factors
  • Thermodynamics
  • Testosterone
  • Substrate Specificity
  • Structure-Activity Relationship
  • Progesterone
  • Models, Theoretical
  • Mathematics
  • Ligands
  • Kinetics