Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones
- J Med Chem. 2007 May 17;50(10):2486-96. doi: 10.1021/jm061329j.
- 1. Discovery Research, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, California 92121, USA. [email protected]
Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel Androgen Receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an Androgen Receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective Androgen Receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.