title: 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.
abstract: 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)
authors.affiliation: Department of Molecular Biochemistry, Glaxo Research Institute, Research Triangle Park, North Carolina 27709.
authors.forename: G
authors.initials: G
authors.lastname: Tian
authors.forename: J D
authors.initials: JD
authors.lastname: Stuart
authors.forename: M L
authors.initials: ML
authors.lastname: Moss
authors.forename: P L
authors.initials: PL
authors.lastname: Domanico
authors.forename: H N
authors.initials: HN
authors.lastname: Bramson
authors.forename: I R
authors.initials: IR
authors.lastname: Patel
authors.forename: S H
authors.initials: SH
authors.lastname: Kadwell
authors.forename: L K
authors.initials: LK
authors.lastname: Overton
authors.forename: T A
authors.initials: TA
authors.lastname: Kost
authors.forename: R A
authors.initials: RA
authors.lastname: Mook
mesh_terms: D058891:5-alpha Reductase Inhibitors; D001665:Binding Sites; D018120:Finasteride / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics
chemical_list: D058891:5-alpha Reductase Inhibitors; D018120:Finasteride