Chemistry

Unlike the ER, which requires a phenolic A ring for high-affinity binding, the PR favors a A4-3-one A-ring structure in an inverted 1fi, 2a-conformation. Some synthetic progestins (especially the 19-nor compounds) display limited binding to glucocorticoid, androgen, and mineralocorti-coid receptors.

One class of agents is similar to progesterone and its metabolite 17a-hydroxyprogesterone (Figure 57-4). Compounds such as hydroxyprogesterone caproate have progestational activity but must be used parenterally due to first-pass hepatic metabolism. Further substitutions at the 6-position of the B ring yield orally active compounds with selective progestational activity, such as MPA and megestrol acetate.

A second class of agents includes 19-nor testosterone derivatives. Lacking the C19 methyl group, these testosterone derivatives display primarily progestational rather than androgenic activity. An ethinyl substituent at C17 decreases hepatic metabolism and yields orally active 19-nortestosterone analogs such as norethindrone, norethynodrel, and ethynodiol diacetate. The activity of the latter two compounds is due primarily to their rapid conversion to norethindrone. These compounds have varying degrees of androgenic activity, and to a lesser extent, estrogenic and antiestrogenic activities.

Replacement of the 13-methyl group of norethindrone with a 13-ethyl substituent yields the gonane norgestrel, which is a more potent progestin than the parent compound but has less andro-genic activity. Other gonanes—including norgestimate, desogestrel, and gestodene (not available in the U.S.)—reportedly have little if any androgenic activity at therapeutic doses.

Newer steroidal progestins include the gonane dienogest; 19-nor-progestin derivatives (e.g., nomegestrol, nestorone, and trimegestone), which have increased selectivity for the PR and less androgenic activity than estranes; and the spironolactone derivative drospirenone, which is used in a combination oral contraceptive. Like spironolactone, drospirenone is also a mineralocorti-coid receptor antagonist.

Agents Similar to Progesterone (Pregnanes)

21CH,

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