SAR of tertiary carbinamine derived BACE1 inhibitors: Role of aspartate ligand amine pKa in enzyme inhibition

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 6, 2010, Pages 1885-1889

  Rajapakse, Hemaka A ^a   Nantermet, Philippe G ^a   Selnick, Harold G ^a   Barrow, James C ^a   McGaughey, Georgia B ^a   Munshi, Sanjeev ^a   Lindsley, Stacey R ^a   Young, Mary Beth ^a   Ngo, Phung L ^a   Katherine Holloway, M ^a   Lai, Ming Tain ^a   Espeseth, Amy S ^a   Shi, Xiao Ping ^a   Colussi, Dennis ^a   Pietrak, Beth ^a   Crouthamel, Ming Chih ^a   Tugusheva, Katherine ^a   Huang, Qian ^a   Xu, Min ^a   Simon, Adam J ^a   Kuo, Lawrence ^a   Hazuda, Daria J ^a   Graham, Samuel ^a   Vacca, Joseph P ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

BACE1; Cell assay; Correlation; Enzyme assay; Tertiary carbinamine

Indexed keywords

AMINE; AMYLOID BETA PROTEIN; ASPARTIC ACID; ASPARTIC ACID DERIVATIVE; BETA SECRETASE; BETA SECRETASE 1; BETA SECRETASE INHIBITOR; METHYLAMINE;

ARTICLE; CATALYSIS; CELL CULTURE; DRUG MECHANISM; DRUG POTENCY; DRUG STABILITY; ENZYME INHIBITION; MOLECULAR INTERACTION; PH; PROTEIN SYNTHESIS; STRUCTURE ACTIVITY RELATION;

AMINES; AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ACID; ASPARTIC ACID ENDOPEPTIDASES; CATALYSIS; ENZYME INHIBITORS; HUMANS; MODELS, MOLECULAR; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77549087611     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.01.137     Document Type: Article

References (17)

1. Nussbaum R.L., and Ellis C.E. N. Eng. J. Med. 348 (2003) 1356
2. Cummings J.L. N. Eng. J. Med. 351 (2004) 56
3. 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
4. Hamada Y., and Kiso Y. Expert Opin. Drug Disc. 4 (2009) 391
5. Rajapakse H.A., Nantermet P.G., Selnick H.G., Munshi S., McGaughey G.B., Lindsley 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
6. Nantermet P.G., Rajapakse H.A., Stanton M.G., Stauffer S.R., Barrow J.C., Gregro A.R., Moore K.P., Steinbeiser M.A., Swestock J., Selnick H.G., Graham S.L., McGaughey G.B., Colussi D., Lai M.-T., Sankaranarayanan S., Simon A.J., Munshi S., Cook J.J., Holahan M.A., Michener M.S., and Vacca J.P. Chem. Med. Chem. 4 (2009) 37
7. Amyloid precursor protein (APP) modified to the NFEV sequence at the site of proteolysis was used in our assays. 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
8. Mastrolorenzo A., Rusconi S., Scozzafava A., and Supuran C.T. Expert Opin. Ther. Patents 16 (2006) 1067
9. For a review on brain penetration by small molecules, see. Hitchcock C.A., and Pennington L.D. J. Med. Chem. 49 (2006) 7559
10. Macrocyclization of inhibitor 20 afforded improved stability, but not sufficient for further development of this lead. See. Lindsley S.R., Moore K.P., Rajapakse H.A., 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.L., Vacca J.P., and Nantermet P.G. Bioorg. Med. Chem. Lett. 17 (2007) 4057
11. X-ray co-crystals obtained with furan linked inhibitors bearing alternate isophalimide substituents indicate that the furan and oxadiazole heterocycles overlay closely, with similar dihedral angles between the five-membered heterocycle and central aryl core.
12. Stachel S.J., Coburn C.A., Rush D., Jones K.L.G., Zhu H., Rajapakse H., Graham S.L., Simon A., Holloway K.M., Allison T.J., Munshi S.K., Espeseth A.S., Zuck P., Colussi D., Wolfe A., Pietrak B.L., Lai M.-T., and Vacca J.P. Bioorg. Med. Chem. Lett. 19 (2009) 2977
13. Stauffer S.R., Stanton M.G., Gregro A.G., Steinbeiser M.A., Shaffer J.R., Nantermet P.G., Barrow J.C., Rittle K.E., Colussi D., Espeseth A.S., Lai M.-T., Pietrak B.L., Holloway K.M., McGaughey G.B., Munshi S.K., Hochman J.H., Simon A.J., Selnick H.G., Graham S.L., and Vacca J.P. Bioorg. Med. Chem. Lett. 17 (2007) 1788
14. Hydroxyethylamine and tertiary carbinamine derived BACE1 inhibitors, as well as inhibitors described in Refs. 10 and 11 were included in the data described in Figure 2.
15. a of 8.2 is over 90% protonated at the same pH.
16. Potency in our cell-based assay correlated with in vivo efficacy observed with CSF Aβ lowering in our CMP rhesus model.
17. Turner P.R., O'Connor K., Tate W.P., and Abraham W.C. Prog. Neurobiol. 70 (2003) 1