Medicinal Chemistry

androgen that has been useful in the treatment of breast cancer in young women is the
2-methyl derivative of testosterone propionate (5.53).

5.10.1 Androgens: Molecular Action

The receptor-mediated molecular action of androgens differs only slightly from the gen-
eral steroid hormone model described previously, which is based principally on estro-
gens and progesterone. In the prostate, testosterone is reduced enzymatically to DHT,
which then binds with high affinity (KD= 10−^11 M) to a cytosol receptor. The binding of
androgens to the cytosol receptor is a process requiring minutes to several hours.
Molecular “flatness,” especially in the A–B ring area, is a prerequisite for effective bind-
ing, and A–B ciscompounds are therefore inactive; accessory binding sites for a 7α-
methyl group seem to be present, which strengthens the binding; the 17β-hydroxyl group
is essential for activity. The intracellular cytosol steroid receptor is bound to stabilizing
proteins such as heat shock protein 90 (Hsp90); when the cytosol receptor binds to a
molecule of steroid, the resulting steroid–receptor cytosol complex becomes unstable
and releases the stabilizing proteins (Hsp90). The steroid–receptor complex then enters
the nucleus, binding to a specific sequence of nucleotides (androgen response element)
on a gene, thus regulating transcription by RNA polymerase II and associated transcrip-
tion factors. The resulting mRNA is exported to the cytoplasm for the production of pro-
tein that enables the final androgen response. The genomic effects of androgens arise
principally from proteins synthesized in response to RNA transcribed by a responsive
gene; however, some of the genomic effects are indirect and are mediated by the
autocrine and paracrine effects of autocoids such as growth factors, lipids, glycolipids,
and cytokines produced by neighboring cells, likewise induced by hormonal action.

5.10.2 Antiandrogens

Antiandrogens such as cyproterone acetate (5.54) or the nonsteroidal flutamide (5.55,
a substituted anilide) are competitive antagonists on the cytosol receptor. They do not
prevent DHT formation; rather, they inhibit the nuclear retention of DHT in the
prostate. They cause feminization in male fetuses and decrease libido in males.
Cyproterone is also an active progestogen. In men, antiandrogens are used commonly
in the treatment of prostatic cancer and uncommonly to inhibit sex drive in “hypersex-
uality”; in women, antiandrogens are used to treat virilization. Bicalutamide (5.56) and
nilutamide (5.57) are potent, orally active antiandrogens that may be used in the treat-
ment of metastatic prostate carcinoma.
Finasteride (5.58), a steroid-like enzyme inhibitor, represents an alternative approach
to antiandrogens. Finasteride inhibits the 5α-reductase-catalyzed conversion of testos-
terone to DHT. In those tissues in which DHT is the active androgenic species (e.g.,
prostate), the androgenic stimulus is reduced; in those tissues in which testosterone is the
active androgenic species (e.g., muscle), the androgenic influence is minimally affected.

5.10.3 Androgens and Male Contraception

Male contraception, involving the suppression of spermatogenesis, is an intensely
investigated area, but there have been few positive results that could be used on a practical

330 MEDICINAL CHEMISTRY