Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 21, 2007, Pages 5831-5835

  Moore, Keith P ^a   Zhu, Hong ^a   Rajapakse, Hemaka A ^a   McGaughey, Georgia B ^a   Colussi, Dennis ^a   Price, Eric A ^a   Sankaranarayanan, Sethu ^a   Simon, Adam J ^a   Pudvah, Nicole T ^a   Hochman, Jerome H ^a   Allison, Timothy ^a   Munshi, Sanjeev K ^a   Graham, Samuel L ^a   Vacca, Joseph P ^a   Nantermet, Philippe G ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

10s loop; Alzheimer's disease; BACE 1; Glycine 230; Macrocyclic N arylation; Macrolactone; Negishi coupling; P gp efflux pump; Tertiary carbinamine

Indexed keywords

AMIDE; BETA SECRETASE INHIBITOR; GLYCOPROTEIN P; METHYLAMINE;

ALZHEIMER DISEASE; ARTICLE; DRUG PENETRATION; DRUG POTENCY; DRUG STRUCTURE;

AMINES; AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ENDOPEPTIDASES; BRAIN; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; MODELS, MOLECULAR;

EID: 34548855068     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.08.040     Document Type: Article

References (26)

1. Nussbaum R.L., and Ellis C.E. N. Eng. J. Med. 348 (2003) 1356
2. Stachel S.J., and Vacca J.P. Curr. Topic Med. Chem. 6 (2006) 551 and following articles
3. Cummings J.L. N. Eng. J. Med. 351 (2004) 56
4. Roberds S.L., Anderson J., Basi G., Bienkowski M.J., Branstetter D.G., Chen K.S., Freedman S., Frigon N.L., Games D., Hu K., Johnson-Wood K., Kappenman K.E., Kawabe T., Kola I., Kuehn R., Lee M., Liu W., Motter R., Nichols N.F., Power M., Robertson D.W., Schenk D., Schoor M., Shopp G.M., Shuck M.E., Sinha S., Svensson K.A., Tatsuno G., Tintrup H., Wijsman J., Wright S., and McConlogue L. Hum. Mol. Genet. 10 (2001) 1317
5. Durham T., and Shepherd T. Curr. Opin. Drug Dis. Dev. 9 (2006) 776
6. Guo T., and Hobbs D.W. Curr. Med. Chem. 13 (2006) 1811
7. Ziora Z., Kimura T., and Kiso Y. Drug Future 31 (2006) 53
8. Beher D., and Graham S.L. Expert Opin. Investig. Drugs 14 (2005) 1385
9. Gosh A.K., Kumaragurubaran N., and Tang J. Curr. Topics Med. Chem. 5 (2005) 1609
10. Thompson L.A., Bronson J.J., and Zusi C. Curr. Pharma. Des. 11 (2005) 3383
11. Rajapakse H.R., Nantermet P.G., Selnick H.G., Munshi S., McGaughey G.B., Lindlsey S.R., Young M.B., Lai M.T., Espeseth A.S., Shi X.P., Colussi D., Pietrak B., Crouthamel M.C., Tugusheva K., Huang Q., Xu M., Simon A.J., Kuo L., Hazuda D.J., Graham S., and Vacca J.P. J. Med. Chem. 49 (2006) 7270
12. Lindsley S.R., Moore K.P., Rajapakse H.R., Selnick H.G., Young M.B., Zhu H., Munshi S., Kuo L., McGaughey G.B., Colussi D., Crouthamel M.C., Lai M.T., Pietrak B., Price E.A., Sankaranarayanan S., Simon A.J., Seabrook G.R., Hazuda D.J., Pudvah N.T., Hochman J.H., Graham S., Vacca J.P., and Nantermet P.G. Bioorg. Med. Chem. Lett. 17 (2007) 4057
13. Hochman J.H., Yamazaki M., Ohe T., and Lin J.H. Curr. Drug Met. 3 (2002) 257
14. Yamazaki M., Neway W.E., Ohe T., Chen I.-W., Rowe J.F., Hochman J.H., Chiba M., and Lin J.H. J. Pharmacol. Exp. Ther. 296 (2001) 723
15. Shi X.-P., Tugusheva K., Bruce J.E., Lucka A., Chen-Dodson E., Hu B., Wu G.-X., Price E., Register R.B., Lineberger J., Miller R., Tang M.-J., Espeseth A., Kahana J., Wolfe A., Crouthamel M.-C., Sankaranarayanan S., Simon A., Chen L., Lai M.-T., Pietrak B., DiMuzio J., Li Y., Xu M., Huang Q., Garsky V., Sardana M.K., and Hazuda D.J. J. Alzheimer's Dis. 7 (2005) 139
16. Black W.C., Bayly C.I., Davis D.E., Desmarais S., Falgueyret J., Léger S., Li C., Massé F., McKay D.J., Palmer J.T., Percival M.D., Robichaud J., Tsou N., and Zamboni R. Bioorg. Med. Chem. Lett. 15 (2005) 4741
17. -6 cm/s for both Ref. 6.
18. 1 aryl group is known to improve inhibitory potency against BACE-1 by 2-fold at best (unpublished results) and is expected to have no significant impact on P-gp susceptibility.
19. Stauffer S.R., Stanton M.G., Gregro A.R., Steinbeiser M.A., Nantermet P.G., Barrow J.C., Rittle K.E., Colussi D., Espeseth A.S., Lai M.T., Pietrak B., Holloway M.K., McGaughey G.B., Munshi S., Hochman J.H., Simon A.J., Selnick H.G., Graham S., and Vacca J.P. Bioorg. Med. Chem. Lett. 17 (2007) 1788
20. 50 calculations from mixtures Refs. 5,12.
21. 3 amide tertiary carbinamine inhibitors (S) Ref. 5. This inversion of configuration is likely allowed by the increased conformational flexibility introduced in the chain when switching from an amide to ethylene linker. Only one of the other three diastereoisomers displayed inhibitory potency at 17 μM. This isomer most likely has the correct R configuration at the tertiary carbinamine center and the S configuration at the γ-position.
22. Brain penetration was assessed from mice brain homogenates, two hours post i.p. dosing in 25% DMSO/75% PEG300, at 30 mpk.
23. McGaughey G.B., Colussi D., Graham S.L., Lai M., Munshi S., Nantermet P.G., Pietrak B., Rajapakse H.A., Selnick H.G., Stauffer S.R., and Holloway M.K. Bioorg. Med. Chem. Lett. 17 (2007) 1117
24. For experimental details, see Supplemental material, Nantermet, P. G.; Rajapakse, H. A.; Selnick, H. G.; Lindsley, S. R.; Moore, K. P.; Stachel, S. J. WO2006055434, and Rajapakse, H. A.; Nantermet, P. G.; Selnick, H. G.; Moore, K. P.; WO2006057983.
25. Nelson D.W., Owens J., and Hiraldo D. J. Org. Chem. 66 (2001) 2572
26. Stauffer S.R., and Steinbeiser M.A. Tetrahedron Lett. 46 (2005) 2571