Abstract
RMI 18,341 (5α,20-R)-4-diazo-21-hydroxy-20-methylpregnan-3-one, was designed to be an enzyme-activated irreversible inhibitor of testosterone 5α-reductase. It produced time-dependent, apparently first-order inactivation of the enzyme, which can be antagonized by substrate, indicative of irreversible inactivation occurring at the enzyme active site. Unlike conventional 5α-steroids, RMI 18,341 has a high affinity for the enzyme:apparent K i = 3.5 × 10 −8M. At 25°C, formation of the reversible EI complex is not rate-limiting for enzyme inactivation, and this is expressed as saturation kinetics for the inhibition reaction. RMI 18,341 produces no inhibition of 3α-hydroxysteroid oxidoreductase of rat prostate, in contrast to other 3-keto-5α-steroids. The specificity, irreversibility and high affinity for testosterone 5α-reductase should make RMI 18,341 a useful tool in elucidation of the physiological roles of testosterone metabolites.
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