Nonsteroidal Contraceptive

FROM THE ACS MEETING

Researchers disclosed for the first time at the ACS national meeting in Philadelphia the design, synthesis, and structure of Tanaproget, a nonsteroid that is now in clinical test ing as an oral contraceptive for women.

All oral contraceptives in current use contain steroid-based progesterone receptor (PR) agonists. These agonists tend to interact with other receptors and pathways, leading to side effects that range from nausea, headaches, cramps, tenderness, and pain to mood changes and increased risk of cardiovascular complications.

Tanaproget is a nonsteroid with high PR affinity and greater than 200-fold selectivity for PR over other steroid receptors, which could lead to an improved side-effect profile.

In a Phase I clinical study, Tanaproget was safe and well tolerated. It is now in Phase II trials.

"The idea of a nonsteroidal contraceptive is very exciting," says Catherine M. Lynch, director of general obstetrics and gynecology at the University of South Florida College of Medicine, Tampa. "I will be very interested in what early data have to show and in the outcome of Phase III trials. If it is effective with few side effects, I think it could have a definite place in the contraceptive marketplace."

Principal scientist Andrew Fensome and coworkers at Wyeth Research, Collegeville, Pa., designed the drug. It's a heterocyclic compound with a cyano-N-methylpyrrole appended to an aryloxazinethione ring system.

As part of a structure-activity relationship study, the researchers obtained the first X-ray crystal structure of a nonsteroid bound to PR--work that "helped us understand why the molecule is so potent and to design in additional selectivity," Fensome says