17 beta-(N-tert-butylcarbamoyl)-4-aza-5 alpha-androstan-1-en-3-one is an active site-directed slow time-dependent inhibitor of human steroid 5 alpha-reductase 1.
17 beta-(N-tert-butylcarbamoyl)-4-aza-5 alpha-androstan-1-en-3-one (finasteride), which has been approved for treatment of benign prostatic hyperplasia, is shown here to be a slow time-dependent inhibitor of human steroid 5 alpha-reductase isozyme 1. This inhibition is characterized by an initial, fast step where the inhibitor binds to the enzyme followed by a slow step that leads to a final enzyme-inhibitor complex (EI*). No recovery of activity from this EI* complex was observed after dialysis for 3 days. The formation of EI* is diminished in the presence of a competitive, reversible inhibitor, indicating that the inhibition is active site-directed. At 37 degrees C and pH 7.0, the rate constant for the second, slow inhibition step, k3, is (1.40 +/- 0.04) x 10(-3) s-1 and the pseudo-bimolecular rate constant, k3/Ki, is (4.0 +/- 0.3) x 10(3) M-1 s-1. This latter rate constant is less than the value of 2.7 x 10(5) M-1 s-1 determined for the inhibition of 5 alpha-reductase 2 by finasteride [Faller, B., Farley, D., & Nick, H. (1993) Biochemistry 32, 5705-5710].(ABSTRACT TRUNCATED AT 250 WORDS)
Tian
G
G
Department of Molecular Biochemistry, Glaxo Research Institute, Research Triangle Park, North Carolina 27709.
Stuart
J D
JD
Moss
M L
ML
Domanico
P L
PL
Bramson
H N
HN
Patel
I R
IR
Kadwell
S H
SH
Overton
L K
LK
Kost
T A
TA
Mook
R A
RA
D058891:5-alpha Reductase Inhibitors; D001665:Binding Sites; D018120:Finasteride / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics
D058891:5-alpha Reductase Inhibitors; D018120:Finasteride