- 1-(2-hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitrile derivatives as potent and tissue selective androgen receptor modulators
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We present a novel series of selective androgen receptor modulators (SARMs) which shows excellent biological activity and physical properties. 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)-indoline-4-carbonitriles showed potent binding to the androgen receptor (AR) and activated AR-mediated transcription in vitro. Representative compounds demonstrated diminished activity in promoting the intramolecular interaction between the AR carboxyl (C) and amino (N) termini. This N/C-termini interaction is a biomarker assay for the undesired androgenic responses in vivo. In orchidectomized rats, daily administration of a lead compound from this series showed anabolic activity by increasing levator ani muscle weight. Importantly, minimal androgenic effects (increased tissue weights) were observed in the prostate and seminal vesicles, along with minimal repression of circulating luteinizing hormone (LH) levels and no change in the lipid and triglyceride levels. This lead compound completed a two week rat toxicology study, and was well tolerated at doses up to 100 mg/kg/day, the highest dose tested, for 14 consecutive days.
- Chekler, Eugene L. Piatnitski,Unwalla, Rayomond,Khan, Taukeer A.,Tangirala, Raghuram S.,Johnson, Mark,St. Andre, Michael,Anderson, James T.,Kenney, Thomas,Chiparri, Sue,McNally, Chris,Kilbourne, Edward,Thompson, Catherine,Nagpal, Sunil,Weber, Gregory,Schelling, Scott,Owens, Jane,Morris, Carl A.,Powell, Dennis,Verhoest, Patrick R.,Gilbert, Adam M.
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supporting information
p. 2462 - 2471
(2014/04/17)
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- A simple Cu-catalyzed coupling approach to substituted 3-pyridinol and 5-pyrimidinol antioxidants
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(Chemical Equation Presented) A convenient approach to 3-pyridinols and 5-pyrimidinols via a two-step Cu-catalyzed benzyloxylation/catalytic hydrogenation sequence is presented. The corresponding 3-pyridinamines and 5-pyrimidinamines can be prepared in an analogous sequence utilizing benzylamine in lieu of benzyl alcohol. The radical-scavenging ability of these derivatives are preliminarily explored and reveal that the increased acidities of the pyridinols and pyrimidinols render them susceptible to more significant kinetic solvent effects when compared to phenols.
- Nara, Susheel J.,Jha, Mukund,Brinkhorst, Johan,Zemanek, Tony J.,Pratt, Derek A.
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experimental part
p. 9326 - 9333
(2009/04/06)
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