(1R,2S)-4-(2-Cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile, a potent androgen receptor antagonist for stimulating hair growth and reducing sebum production

Hu, Lufei; Du, Daniel; Hoffman, Jennifer K.; Smith, Yvonne; Fedij, Victor; Kostlan, Catherine R.; Johnson, Theodore R.; Huang, Yun; Kesten, Steven; Harter, William G.; Yue, Wen Song; Li, Jie Jack; Barvian, Nicole C.; Mitchell, Lorna H.; Lei, Huangshu; Lefker, Bruce A.; Carroll, Mathew; Dettling, Danielle; Krieger-Burke, Teresa; Samas, Brian; Yalamanchili, Radhika; Lapham, Kimberly; Pocalyko, David; Sliskovic, Drago R.; Ciotti, Susan; Stoller, Brenda; Hena, Mostofa Abu; Ding, Qizhu; Maiti, Samarendra N.; Stier, Michael A.; Welgus, Howard G.

doi:10.1016/j.bmcl.2007.07.075

Cited by 14 publications

(12 citation statements)

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“…Thus, HheG's enantiopreference opens a new biocatalytic route toward the androgen receptor antagonist (1R,2S)-4-((2-cyanocyclohexyl)oxy)-2-(trifluoromethyl)benzonitrile. 14 In the azidolysis of 2, HheG exhibited an ee value of 40% for the formation of one enantiomer of azidoalcohol 4. To determine the stereoconfiguration of this enantiomer, azidoalcohol 4 was chemically reduced to the corresponding aminoalcohol and further analyzed by chiral GC after derivatization.…”

Section: ■ Introductionmentioning

confidence: 97%

“…In particular, the selective epoxide ring-opening of cyclic epoxides using HHDHs would be of high interest, as this would enable access to chiral synthons for the production of pharmaceuticals such as (1R,2S)-4-((2-cyanocyclohexyl)oxy)-2-(trifluoromethyl)benzonitrile, a potent androgen receptor antagonist. 14 ■ RESULTS AND DISCUSSION Conversion of Cyclic Epoxides by HHDHs. To investigate the activity of new HHDHs toward cyclic epoxides, our 17 previously characterized HHDHs 12 together with the well-known HheC from A. tumefaciens 10 were applied in conversions of cyclohexene oxide ( 2) and (+)-cis/(+)-translimonene oxide (5).…”

Section: ■ Introductionmentioning

confidence: 99%

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HheG, a Halohydrin Dehalogenase with Activity on Cyclic Epoxides

et al. 2017

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Halohydrin dehalogenases (HHDHs) are of biotechnological interest due to their promiscuous epoxide ring-opening activity with a set of negatively charged nucleophiles, enabling the formation of C−C, C−N, or C−O bonds. The recent discovery of HHDH-specific sequence motifs aided the identification of a large number of halohydrin dehalogenases from public sequence databases, enlarging the biocatalytic toolbox substantially. During the characterization of 17 representatives of these phylogenetically diverse enzymes, one HHDH, namely HheG from Ilumatobacter coccineus, was identified to convert cyclic epoxide substrates. The enzyme exhibits significant activity in the azidolysis of cyclohexene oxide and limonene oxide with turnover numbers of 7.8 and 44 s −1 , respectively. As observed for other HHDHs, the cyanide-mediated epoxide ring-opening proceeded with lower rates. Wild-type HheG displays modest enantioselectivity, as the resulting azido-and cyanoalcohols of cyclohexene oxide ring-opening were obtained in 40% enantiomeric excess. These biocatalytic findings were further complemented by the crystal structure of the enzyme refined to 2.3 Å. Analysis of HheG's structure revealed a large open cleft harboring the active site. This is in sharp contrast to other known HHDH structures and aids in explaining the special substrate scope of HheG.

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Section: ■ Introductionmentioning

confidence: 97%

Section: ■ Introductionmentioning

confidence: 99%

HheG, a Halohydrin Dehalogenase with Activity on Cyclic Epoxides

et al. 2017

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“…Thus, the length of SARM administration should not influence the readout as it does when measuring tissue weight. Compared to measuring the weights of [74,75] Testis Spermatogenesis § , gene transcription, mating Yes If possible [76] Hair follicles/sebaceous gland Hair growth, gene transcription Yes Yes [77] Bone BMD (multiple bones), bone strength, gene transcription, quantitative histological and serological markers ¶ Yes Yes [45,48] Skeletal muscle Wet weight, gene transcription, lean body mass, quantitative histological markers # , muscle strength (peak tetanus pressure)…”

Section: Expert Opinionmentioning

confidence: 99%

Improving selective androgen receptor modulator discovery and preclinical evaluation

Jones

2009

Expert Opinion on Drug Discovery

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The SARM field has advanced rapidly, but without a solid foundation of molecular knowledge to inform discovery and preclinical evaluation methods. The field has also taken a narrow view of selectivity, disregarding many androgen-responsive tissues, which could lead to unforeseen and detrimental side effects with chronic administration of SARMs. An investment in basic research could accelerate the discovery of a new generation of more selective and safer SARMs that could be used to treat an expanded range of clinical conditions.

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“…Intensity(a.u) w avelength (nm ) of particles due to the increase of Gd concentration 21 .The absorption value reveals the charge transfer from O 2+ to Ce 4+ energy levels in CeO 2 crystal lattice 22 . The absorption wavelength and their corresponding bandgap energy values are presented in Table 2.…”

Section: Optical Studiesmentioning

confidence: 99%

Hydrothermal Synthesis of Gadolinium (Gd) Doped Cerium Oxide (CeO2) Nanoparticles: Characterization and Antibacterial Activity

Khadar¹,

Balamurugan²,

Devarajan³

et al. 2017

Orient. J. Chem

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This present study has been described the synthesis, characterization and antibacterial activity of gadolinium doped cerium oxide nanoparticles. The nanoparticles were prepared by hydrothermal method with various concentrations of gadolinium ranges from 2 mol% to 8 mol%. The X-ray diffraction (XRD) pattern revealed the face-centered cubic structure with crystalline size of 58.3 nm to 57.4 nm with increasing the concentration of gadolinium (2 mol% to 8 mol%). The Ce-O chemical bonding nature was confirmed using Fourier transform infrared spectrometer (FTIR). The field emission scanning electron microscope (FESEM) exhibited fascinating shapes like cube and square of nanoparticles. UV spectrophotometer used to measure the optical behaviors of CeO 2 nanoparticles. Band-edge absorption of CeO 2 nanoparticles blue shifted upon increasing the gadolinium concentration as compared to undoped CeO 2 nanoparticles. The emission behavior of nanoparticles was examined by photoluminescence (PL) spectroscopy. PL spectra reveals a peak shift of CeO 2 emission upon gadolinium doped due to oxygen defect. The gadolinium doped CeO 2 nanoparticles showed better antibacterial activity against the pathogenic bacteria such as Escherichia coli, Staphylococcus aureus, Bacillus cereus and Salmonella typhi.

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(1R,2S)-4-(2-Cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile, a potent androgen receptor antagonist for stimulating hair growth and reducing sebum production

Cited by 14 publications

References 14 publications

HheG, a Halohydrin Dehalogenase with Activity on Cyclic Epoxides

HheG, a Halohydrin Dehalogenase with Activity on Cyclic Epoxides

Improving selective androgen receptor modulator discovery and preclinical evaluation

Hydrothermal Synthesis of Gadolinium (Gd) Doped Cerium Oxide (CeO2) Nanoparticles: Characterization and Antibacterial Activity

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