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

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 21, 2007, Pages 5983-5988

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

^a PFIZER INC   (United States)

^b NAEJA Pharmaceutical Inc   (Canada)

Author keywords

Aryl ether; Hair growth; Sebum reduction

Indexed keywords

4 (2 CYANOCYCLOHEXYLOXY) 2 TRIFLUOROMETHYLBENZONITRILE; 4 [3 (4 HYDROXYBUTYL) 4,4 DIMETHYL 2,5 DIOXO 1 IMIDAZOLIDINYL] 2 TRIFLUOROMETHYLBENZONITRILE; ANTIANDROGEN; BICALUTAMIDE; FLUTAMIDE; NILUTAMIDE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG SYNTHESIS; HAIR GROWTH; MALE; MOUSE; NONHUMAN; SEBUM SECRETION; SYRIAN HAMSTER;

ANDROGEN ANTAGONISTS; ANIMALS; CRICETINAE; HAIR; HYDROCARBONS, FLUORINATED; MALE; MESOCRICETUS; MICE; MODELS, MOLECULAR; NITRILES; SEBUM;

MESOCRICETUS AURATUS;

EID: 34548847159     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.07.075     Document Type: Article

References (27)

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14. 50).
15. 50 < 200 nM). Compounds were selected for further testing in a whole cell functional assay (AR Cell assay) for their ability to antagonize the effects of DHT on the androgen receptor. The androgen receptor cellular functional assay was conducted in a human breast tumor cell line expressing androgen receptor (MDA-MB453-MMTV clone 54-19). The cell line is a stably transfected cell line with MDA-MB453 cell background. A MMTV minimal promoter containing Androgen Response Element (ARE) was first cloned in front of a firefly luciferase receptor gene. Then the cascade was cloned into a transfection vector pUV120puro. Electroporation was used for transfecting MDA-MB-453 cells and a puromycin resistant stable cell line was selected.
16. The general procedure: to a Bohdan mini-block reaction tube containing a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (0.3 mmol) and the appropriate cycloalkane-halide (0.3 mmol) in anhydrous THF (1.3 mL) was added a 0.6 M slurry of sodium hydride in anhydrous THF (2 equiv, 0.6 mmol). The Bohdan mini-block was capped and the reaction mixture was shaken at ambient temperature for 16 h. Five-hundred microliters of methanol and 100 mg of MP-TsOH (4.07 mmol/g, 1.35 equiv, 0.41 mmol) were added and the reaction mixture was shaken at ambient temperature for 20 h. Reaction mixture was filtered and concentrated utilizing a Genevac HT-12. Sample was purified via reverse phase HPLC.
17. 2). (trans)-(+)-(1S,2R)-4-(2-Cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzoni trile (7): Chiral HPLC Retention Time: 14 min.
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19. 2), ee 98%. The retention time of other diastereomer was 8 min.
20. 2), ee 99.2%. The retention time of other diastereomer was 18.6 min.
21. 1. The refined structure fits well to the data with a final R1 index of 9% and no missing or misplaced electron density observed in the final difference Fourier. The structure is proof of relative configuration between the stereo centers.
22. 2). Ten mice were used in each experimental group. The treatment regimen was twice daily (BID) application for 4 weeks, 5 days/week from Monday to Friday. Local irritation was recorded before each application and hair growth scores were recorded every other day. After 4 weeks of treatment, mice were further observed for one more week during which hair growth and skin irritation were scored every other day. The scale used for scoring hair growth was: 0 = no hair growth, pink skin; 1 = skin color changes from pink to gray or black without visible hair growth, indicating the onset of anagen; 2 = sparse or diffuse short hair growth; 3 = dense, normal coat hair. A reference androgen receptor antagonist (RU-58841, 4) was included in every study.
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26. Pharmacokinetics in rats: male Sprague-Dawley rats (n = 2) were administered a 1 mg/kg intravenous dose of 8 as a 5 min infusion at a dose volume of 2.9 mL/kg. Compound 8 was formulated as a solution in a vehicle consisting of 5% N,N-dimethylacetamide, 40% propylene glycol, and 55% saline. Serial blood samples were collected from each rat over a 24 h period postdose. Plasma concentrations of 8 were determined using a LC/MS/MS method, and pharmacokinetic parameters were determined from the plasma concentration-time data using noncompart-mental methods.
27. 2/h (n = 14 replicates).