Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named “ligand dependent transcription factors” (R. M. Evans, Science, 240:889, 1988). Steroid receptors are a recognized subset of the IRs, including androgen receptor (AR), progesterone receptor (PR), estrogen receptor (ER), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand, which has the ability to selectively bind to the IR in a way that affects gene transcription.
The natural hormones for steroid receptors have been known for a long time, such as testosterone for AR and progesterone for PR. A synthetic compound that binds to an IR and mimics the effect of the native hormone is referred to as an “agonist”, while a compound that inhibits the effect of the native hormone is called an “antagonist”. The term “modulators” refers to a group of compounds that have a spectrum of activities from agonist, partial agonist to antagonist.
Androgen and progesterone receptor modulators are known to play an important role in health of both men and women. For example, AR antagonists, such as cyproterone acetate, flutamide and casodex, are useful in the treatment of prostatic hyperplasia and cancer of the prostate. AR agonists, such as fluoxymesterone, are used in the treatment of hypogonadism. PR agonists, such as medroxyprogesterone acetate, are used in birth control formulations in combination with the female hormone estrogen or a synthetic estrogen analogue. Further, antagonists of PR are potentially useful for contraception and in the treatment of chronic disorders, such as certain hormone dependent cancers of the breast, ovary and uterus. Due to increased life expectancies, development of tissue selective, safer, orally active AR and PR modulators are desirable to improve quality of life.
A group of hydroquinoline derivatives was recently described as AR and PR modulators (e.g., U.S. Pat. Nos. 5,688,808, 5,688,810, 5,693,646, 5,693,647, 5,696,127, 5,696,130). This group of AR and PR modulators was developed by using cell-based high-throughput assays, termed cotransfection assays. Amino- or hydroxy-trifluoromethylquinolones or coumarins have been described as fluorescent markers in biological systems. See, e.g., U.S. Pat. No. 4,505,852 and E. R. Bissel et al., “Synthesis and Chemistry of 7-Amino-4-(trifluoromethyl)coumarin and Its Amino Acid and Peptide Derivatives”, J. Org. Chem., 45:2283, 1980). Analogues of quinolone, oxindole, benzooxazinone derivatives have been described as cardiotonic agents. See, e.g., U.S. Pat. Nos. 3,993,656; 4,415,572; 4,427,654; 4,710,507; 4,728,653; 4,933,336; 5,081,242.