Discovery of non-steroidal mifepristone mimetics: Pyrazoline-based PR antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 13, 2005, Pages 3203-3206

  Jones, David G ^a   Liang, Xi ^a   Stewart, Eugene L ^a   Noe, Robert A ^a   Kallander, Lara S ^a   Madauss, Kevin P ^a   Williams, Shawn P ^a   Thompson, Scott K ^a   Gray, David W ^a   Hoekstra, William J ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ABORTIVE AGENT; ANDROGEN RECEPTOR; ANTIGESTAGEN; GLUCOCORTICOID RECEPTOR; MIFEPRISTONE; MOMETASONE FUROATE; NORETHISTERONE; PROGESTERONE; PROGESTERONE RECEPTOR; PYRAZOLINE DERIVATIVE; STEROID RECEPTOR;

ARTICLE; DRUG ACTIVITY; DRUG SYNTHESIS; ENDOMETRIOSIS; MOLECULAR MODEL; SEQUENCE HOMOLOGY;

CELL LINE; FLUORESCENT DYES; HUMANS; LIGANDS; MIFEPRISTONE; MODELS, MOLECULAR; MOLECULAR MIMICRY; PROTEIN BINDING; PYRAZOLES; RECEPTORS, PROGESTERONE; TRANSFECTION;

EID: 20444415985     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.05.001     Document Type: Article

References (19)

1. P.W. Ashok, P.T. Wagaarachchi, and A. Templeton Curr. Med. Chem. Immun. Endocr. Metab. Agents 2 2002 71
2. H. Hess-Stumpp, J. Hoffmann, and U. Fuhrmann Drugs Future 27 2002 1113
3. I.M. Spitz, and K. Chwalisz Steroids 65 2000 807
4. M.C. Pike, and R.K. Ross Steroids 65 2000 659
5. L. Zhi, C.M. Tegley, B. Pio, J.P. Edwards, M. Motamedi, T.K. Jones, K.B. Marschke, D.E. Mais, B. Risek, and W.T. Schrader J. Med. Chem. 46 2003 4104
6. L. Zhi, J.D. Ringgenberg, J.P. Edwards, C.M. Tegley, S.J. West, B. Pio, M. Motamedi, T.K. Jones, K.B. Marschke, D.E. Mais, and W.T. Schrader Bioorg. Med. Chem. Lett. 13 2003 2075
7. S.P. Williams, and P.B. Sigler Nature 393 1998 392
8. A.K. Shiau, D. Barstad, P.M. Loria, L. Cheng, P.J. Kushner, D.A. Agard, and G.L. Greene Cell 95 1998 927
9. M.H. Lambert Practical Application of Computer-Aided Drug Design 1997 Marcel-Dekker New York pp. 243-303
10. S. Palmer, C.A. Campen, G.F. Allan, P. Rybczynski, D.H. Johnson, A. Hutchins, P. Kraft, M. Kiddoe, M.-T. Lai, E. Lombardi, P. Pedersen, G. Hodgen, and D.W. Combs J. Steroid Biochem. Mol. Biol. 75 2001 33
11. D.W. Combs, K. Reese, L.A.M. Cornelius, J.W. Gunnett, E.V. Cryan, K.S. Granger, J.J. Jordan, and K.T. Demarest J. Med. Chem. 38 1995 4880
12. Protein Data Bank number 1sr7. For a reference, see: K.P. Madauss, S.-J. Deng, R.J.H. Austin, M.H. Lambert, I. McLay, J. Pritchard, S. Short, E.L. Stewart, I. Uings, and S.P. Williams J. Med. Chem. 47 2004 3381
13. A. Levai J. Heterocyclic Chem. 39 2002 1 and references cited therein
14. 4, and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with EtOAc/hexane (15/85) to give pyrazoline 7a
15. Enantiomerically enriched products were isolated from racemates using a 10-μm Chiralpak AD stati onary phase (21 × 250 mm) and 10% MeOH/water mobile phase at a flow rate of 50 ml/min with detection at 254 nm
16. -1 resolution in carbon tetrachloride at a concentration of 20 mg/ml. For a reference, see: F.J. Devlin, P.J. Stephens, C. Osterle, K.B. Wiberg, J.R. Cheeseman, and M.J. Frisch J. Org. Chem. 67 2002 8090 and references cited therein
17. i
18. 50 = 9.8, 100% efficacy). Comparable potencies and efficacies were observed for a limited set of compounds in a T47D cell alkaline phosphatase assay
19. Details will be reported in a forthcoming full paper