Novel orally active morpholine N-arylsulfonamides γ-secretase inhibitors with low CYP 3A4 liability

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 21, 2009, Pages 6032-6037

  Josien, Hubert ^a   Bara, Thomas ^a   Rajagopalan, Murali ^a   Clader, John W ^a   Greenlee, William J ^a   Favreau, Leonard ^a   Hyde, Lynn A ^a   Nomeir, Amin A ^a   Parker, Eric M ^a   Song, Lixin ^a   Zhang, Lili ^a   Zhang, Qi ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Secretase; Alzheimer's disease; CYP 3A4; Inhibitor; Morpholine; Sulfonamide

Indexed keywords

2,6 DISUBSTITUTED MORPHOLINE N ARYLSULFONAMIDE; AMYLOID BETA PROTEIN; CYTOCHROME P450 3A4; GAMMA SECRETASE INHIBITOR; MORPHOLINE DERIVATIVE; PIPERIDINE DERIVATIVE; SULFONAMIDE; UNCLASSIFIED DRUG;

AMINATION; ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; IC 50; LIPOPHILICITY; MOLECULAR WEIGHT; MOUSE; NONHUMAN; RAT;

ADMINISTRATION, ORAL; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; CYTOCHROME P-450 CYP3A; DISEASE MODELS, ANIMAL; ENZYME INHIBITORS; HUMANS; MICE; MICE, TRANSGENIC; MORPHOLINES; RATS; SULFONAMIDES;

MUS;

EID: 71749107570     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.09.055     Document Type: Article

References (24)

1. McDowell I. Aging 13 (2001) 143
2. Debaggio T. Losing my Mind: an Intimate Look at Life with Alzheimer's (2002), Free Press, Simon and Schuster
3. Pallas M., and Camins A. Curr. Pharmacol. Des. 12 (2006) 4389
4. Hardy J., and Selkoe D.J. Science 297 (2002) 353
5. Wolfe M.S. Curr. Top. Med. Chem. 8 (2008) 2
6. Hills I.D., and Vacca J.P. Curr. Opin. Drug Discov. Dev. 10 (2007) 383
7. Churcher I. Curr. Top. Med. Chem. 6 (2006) 579
8. Vila J. J. Cell. Mol. Med. 12 (2008) 258
9. Run X., Liang Z., Zhang L., Iqbal K., Grundke-Iqbal I., and Gong C.X. J. Alzheimer Dis. 16 (2009) 619
10. Williams M. Curr. Opin. Invest. Drugs 10 (2009) 23
11. Gotz J., Ittner L.M., and Lim Y.A. Cell. Mol. Life Sci. 66 (2009) 1321
12. Wolfe M.S. Curr. Alzheimer Res. 5 (2008) 158
13. Imbimbo B.P., Hutter-Paier B., Villetti G., Facchinetti F., Cenacchi V., Volta R., Lanzillotta A., Pizzi M., and Windisch M. Br. J. Pharmacol. 15 (2009) 982
14. Pissarnitski D. Curr. Opin. Drug Discov. Dev. 10 (2007) 392
15. Imbimbo B.P. Curr. Top. Med. Chem. 8 (2008) 54
16. Hyde L.A., McHugh N.A., Chen J., Zhang Q., Manfra D., Nomeir A.A., Josien H., Bara T., Clader J.W., Zhang L., Parker E.M., and Higgins G.A. J. Pharmacol. Exp. Ther. 319 (2006) 1133
17. Pissarnitski D.A., Asberom T.A., Bara T.A., Buevich A.V., Clader J.W., Greenlee W.J., Gusik H.S., Josien H.B., Li W., McEwan M., McKittrick B.A., Nechuta T.L., Parker E.M., Sinning L., Smith E.M., Song L., Vaccaro H.A., Voigt J.H., Zhang L., Zhang Q., and Zhao Z. Bioorg. Med. Chem. Lett. 17 (2007) 57
18. Josien H., Bara T., Rajagopalan M., Asberom T., Clader J.W., Favreau L., Greenlee W.J., Hyde L.A., Nomeir A.A., Parker E.M., Pissarnitski D.A., Song L., Zhang L., Zhang Q., and Zhao Z. Bioorg. Med. Chem. Lett. 17 (2007) 5330
19. Li H., Asberom T., Bara T.A., Clader J.W., Greenlee W.J., Josien H.B., McBriar M.D., Nomeir A., Pissarnitski D.A., Rajagopalan M., Xu R., Zhao Z., Song L., and Zhang L. Bioorg. Med. Chem. Lett. 17 (2007) 6290
20. Muthusamy S., Babu S.A., and Gunanathan C. Tetrahedron Lett. 43 (2002) 3133
21. Caplar V., Lisini A., Kajfez F., Kolbah D., and Sunjic V. J. Org. Chem. 43 (1978) 1355
22. Calmes M., Daunis J., Escale F., Jacquier R., and Roumestant M.-L. Tetrahedron: Asymmetry 1643 (1994) 5
23. Kulinkovich O., Sviridov S.V., and Vasilevski D.A. Synthesis (1991) 234
24. The following route was used prior to steps l-m of Scheme 2:{A figure is presented}This route used processes derived from: Pine, S. H. Org. React. 1993, 43, 1; Denmark, S. E.; Beutner, G. In Cycloaddition Reactions in Organic Synthesis; Kobayashi, S., Jorgensen, K. A., Eds; Wiley-VCH Verlag GmbH & Co KGaA: Weinheim, Germany, 2002; p 85.