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. Epub 2007 Apr 17.

Abstract

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.

MeSH terms

  • Anabolic Agents / chemical synthesis
  • Anabolic Agents / chemistry
  • Anabolic Agents / pharmacology
  • Androgens
  • Animals
  • Binding, Competitive
  • Cell Line, Tumor
  • Humans
  • Male
  • Muscle, Skeletal / anatomy & histology
  • Muscle, Skeletal / drug effects
  • Organ Size / drug effects
  • Oxazines / chemical synthesis*
  • Oxazines / chemistry
  • Oxazines / pharmacology
  • Prostate / anatomy & histology
  • Prostate / drug effects
  • Quinolones / chemical synthesis*
  • Quinolones / chemistry
  • Quinolones / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Androgen / drug effects*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transcriptional Activation / drug effects

Substances

  • 1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-(1,4)oxazino(3,2-g)quinolin-7-one
  • Anabolic Agents
  • Androgens
  • Oxazines
  • Quinolones
  • Receptors, Androgen