17 beta-hydroxysteroid dehydrogenase: Inhibitors and inhibitor design

In designing 17β-HSD inhibitors attempts have been made to exploit the enzyme's catalytic mechanism by testing compounds that give rise to enzyme-generated affinity alkylators (latent steroid Michael acceptors). This field is still ripe for development; no attempt has been made to synthesize transition-state analogs based on bisubstrate analogs, and appropriate D-ring fused pyrazoles have not been synthesized as potential activated ternates. The effect of electron-withdrawal and -donation on the turnover and reactivity of steroid latent and active Michael acceptors has not been systematically explored. Even though it has been documented that 17β-HSD will bind non-steroidal estrogens and antiestrogens as competitive inhibitors, no attempts have been made to exploit this finding by using these compounds as leads for the synthesis of either more potent reversible inhibitors or non-steroidal suicide substrates for 17β-HSD. The availability of a three-dimensional structure for estrogenic 17β-HSD Type I can now be exploited to rationally design enzyme inhibitors. Nearly all the studies described have been performed on 17β-HSD Type I, but the availability of cDNA clones for Type I-IV 17β-HSDs provides the opportunity to develop compounds that will selectively block both estrogen and androgen biosynthesis.