Novel Series of Potent, Nonsteroidal, Selective Androgen Receptor Modulators Based on 7H-[1,4]Oxazino[3,2-g]quinolin-7-ones
- 17 April 2007
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 50 (10) , 2486-2496
- https://doi.org/10.1021/jm061329j
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.Keywords
This publication has 16 references indexed in Scilit:
- A bioisosteric approach to the discovery of indole carbinol androgen receptor ligandsBioorganic & Medicinal Chemistry Letters, 2006
- Discovery of 6-N,N-Bis(2,2,2-trifluoroethyl)amino- 4-trifluoromethylquinolin-2(1H)-one as a Novel Selective Androgen Receptor ModulatorJournal of Medicinal Chemistry, 2006
- Andropause: invention, prevention, rejuvenationTrends in Endocrinology & Metabolism, 2005
- Design, Synthesis, and Biological Characterization of Metabolically Stable Selective Androgen Receptor ModulatorsJournal of Medicinal Chemistry, 2004
- Discovery of a Potent, Orally Active, Nonsteroidal Androgen Receptor Agonist: 4-Ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl)-8-pyridono[5,6-g]- quinoline (LG121071)Journal of Medicinal Chemistry, 1999
- Synthesis and Biological Activity of a Novel Series of Nonsteroidal, Peripherally Selective Androgen Receptor Antagonists Derived from 1,2-Dihydropyridono[5,6-g]quinolinesJournal of Medicinal Chemistry, 1998
- Androgens in Men — Uses and AbusesNew England Journal of Medicine, 1996
- The Intracellular Receptor and Signal Transducers and Activators of Transcription Factor Superfamilies: Novel Targets for Small-Molecule Drug DiscoveryJournal of Medicinal Chemistry, 1995
- A GENERAL AND CONVENIENT SYNTHESIS OF 2H-1,4-BENZOXAZIN-3(4H)-ONESOrganic Preparations and Procedures International, 1982
- Nybomycin. VII. Preparative routes to nybomycin and deoxynybomycinJournal of the American Chemical Society, 1973