Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms.

As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.

A bioisosteric approach to the discovery of indole carbinol androgen receptor ligands.

Two potential bioisosteres of the nonsteroidal antiandrogen bicalutamide, an imidazolidinone and an indole, were synthesized and tested for their androgen receptor binding. Indole was discovered to be a suitable bioisostere for the acyl anilide moiety in the parent compound. Several analogs in the indole series were found to be 10-fold better than bicalutamide in binding to the recombinant androgen receptor binding domain.

Novel chromene-derived selective estrogen receptor modulators useful for alleviating hot flushes and vaginal dryness.

A novel SERM (selective estrogen receptor modulators), 1-(R), a chromene-derived bisbenzopyran, was discovered to alleviate hot flushes and effectively increase vaginal fluidity in rats. Moreover, 1-(R) was found to have beneficial effects on plasma cholesterol and bone metabolism while maintaining antiestrogenic activity in the uterus. The biological profile of its enantiomer 1-(S) was also evaluated.

Discovery of indole-containing tetracycles as a new scaffold for androgen receptor ligands.

A novel series of tetracyclic indoles have been designed, synthesized and evaluated as androgen receptor (AR) ligands. Studies of structure-activity relationships (SARs) were investigated, which led to some compounds in this series as strong binders to androgen receptors.

Molecular properties and preclinical pharmacology of JNJ-1250132, a steroidal progesterone receptor modulator that inhibits binding of the receptor to DNA in vitro.

Progesterone receptor modulators have diverse potential therapeutic uses, including the treatment of endometriosis, uterine fibroids and breast cancer. Here we describe the molecular properties and preclinical pharmacology of a new steroidal progestin antagonist, JNJ-1250132. The compound is a high affinity ligand for the progesterone receptor, possessing cross-reactivity with other steroid receptors comparable to that of steroidal antagonists such as mifepristone.