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2-Methyl-4-(trifluoromethyl)-1 H-indole-5-carbonitrile is a key intermediate in the synthesis of selective androgen receptor modulators discovered in these laboratories. A practical and convergent synthesis of the title compound starting from 4-nitro-3-(trifluoromethyl)phenol and tert-butyl acetoacetate was developed, including a telescoped procedure for synthesis (without isolation) and Nenitzescu reaction of 2-trifluoromethyl-1,4-benzoquinone. Conversion of the known Nenitzescu indole product to a novel triflate intermediate followed by palladium-catalyzed cyanation afforded a penultimate carbonitrile. Removal of the C-3 tert-butyl ester group on the indole through a decarboxylative pathway completed the synthesis of the title compound in six steps (27% overall yield) from 4-nitro-3-(trifluoromethyl)phenol (five steps, 37% overall yield from tert-butyl acetoacetate). J. Heterocyclic Chem., (2011). [ABSTRACT FROM AUTHOR]

Biomarkers of muscle protein synthesis rate could provide early data demonstrating anabolic efficacy for treating muscle-wasting conditions. Androgenic therapies have been shown to increase muscle mass primarily by increasing the rate of muscle protein synthesis. We hypothesized that the synthesis rate of large numbers of individual muscle proteins could serve as early response biomarkers and potentially treatment-specific signaling for predicting the effect of anabolic treatments on muscle mass. Utilizing selective androgen receptor modulator (SARM) treatment in the ovariectomized (OVX) rat, we applied an unbiased, dynamic proteomics approach to measure the fractional synthesis rates (FSR) of 167-201 individual skeletal muscle proteins in triceps, EDL, and soleus. OVX rats treated with a SARM molecule (GSK212A at 0.1, 0.3, or 1 mg/kg) for 10 or 28 days showed significant, dose-related increases in body weight, lean body mass, and individual triceps but not EDL or soleus weights. Thirty-four out of the 94 proteins measured from the triceps of all rats exhibited a significant, dose-related increase in FSR after 10 days of SARM treatment. For several cytoplasmic proteins, including carbonic anhydrase 3, creatine kinase M-type (CK-M), pyruvate kinase, and aldolase-A, a change in 10-day FSR was strongly correlated (r(2) = 0.90-0.99) to the 28-day change in lean body mass and triceps weight gains, suggesting a noninvasive measurement of SARM effects. In summary, FSR of multiple muscle proteins measured by dynamics of moderate- to high-abundance proteins provides early biomarkers of the anabolic response of skeletal muscle to SARM., (Copyright © 2016 the American Physiological Society.)

A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.