Thiochroman derivative CH4986399, a new nonsteroidal estrogen receptor down-regulator, is effective in breast cancer models.

Background: Tamoxifen, a selective estrogen receptor modulator, and fulvestrant, a selective estrogen receptor down-regulator (SERD), are now available for estrogen receptor-positive breast cancer patients. However, these patients acquire drug-resistance during the treatments. We identified a new orally active nonsteroidal SERD, CH4986399, which is structurally unrelated to fulvestrant and tamoxifen.

Effects of CH4893237, a new orally active estrogen receptor downregulator, on breast cancer xenograft models with low serum estrogen levels.

We compared the antitumor efficacy and estrogen receptor (ER) degradation of CH4893237, a new orally active selective ER downregulator, with fulvestrant and tamoxifen in human breast cancer xenografts with low levels of serum estrogen (E2) (50.6, 22.9 and <16.

Newly discovered orally active pure antiestrogens.

In order to develop orally active pure antiestrogens, we incorporated the carboxy-containing side chains into the 7alpha-position of the steroid scaffold and found that 17-keto derivative CH4893237 (12b) functioned as a pure antiestrogen with its oral activity much superior to clinically used pure antiestrogen, ICI182,780. Results from the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing in mice attributed to both improved absorption from the intestinal wall and metabolic stability in liver.

Discovery of thiochroman derivatives bearing a carboxy-containing side chain as orally active pure antiestrogens.

In order to search for alternatives to the sulfoxide moiety in the long side chain of pure antiestrogens, several molecules that may interact with water in a fashion similar to ICI164,384 were designed and it was found that compounds with the carboxy, the sulfamide, or the sulfonamide instead of the sulfoxide moiety also functioned as pure antiestrogens. Interestingly, the compound possessing the carboxy moiety showed superior antiestrogen activity compared to ICI182,780 when dosed orally. Results of the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing attributed to both the improved absorption from the intestinal wall and the metabolic stability of the compound in liver.

Discovery of thiochroman and chroman derivatives as pure antiestrogens and their structure-activity relationship.

In order to develop pure antiestrogens, a series of 7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman and 7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman derivatives with sulfoxide containing side chains at the 4-position were designed, synthesized, and evaluated. Among them, compounds 14b and 24b functioned as pure antiestrogens with the ability to downregulate ER, and their in vitro and in vivo antiestrogen activities were similar to those of ICI182,780. In addition, the structure-activity relationship indicated that the (3RS,4RS)-configuration between the 3- and 4-position, the methyl group at the 3-position, the 9-methylene chain between the scaffold and the sulfoxide moiety, and the terminal perfluoroalkyl moiety play an important role in increasing estrogen receptor binding and oral antiestrogen activities.

Identification of a novel, orally bioavailable estrogen receptor downregulator.

Tamoxifen has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer, but its partial agonist activity is considered to limit the efficacy, and cause tumor flare and endometrial cancer. Fulvestrant, on the other hand, binds and degrades ER, thereby acting as a pure anti-estrogen without partial agonist activity. However, due to its low oral bioavailability, fulvestrant has to be intramuscularly administered to patients, which limits the convenience of the drug, and causes pain and inflammation at the site of injection.