Synthesis and SAR of bis-statine based peptides as BACE 1 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 13, 2004, Pages 3457-3460

  Hu, Baihua ^a   Fan, Kristi Yi ^a   Bridges, Kristie ^a   Chopra, Rajiv ^a   Lovering, Frank ^a   Cole, Derek ^b   Zhou, Ping ^a   Ellingboe, John ^b   Jin, Guixiang ^b   Cowling, Rebecca ^b   Bard, Jonathan ^a  

^a PFIZER INC   (United States)

^b WYETH RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOMETHYLBENZOIC ACID; BETA SECRETASE INHIBITOR; STATINE DERIVATIVE;

AMINO TERMINAL SEQUENCE; ARTICLE; CONFORMATIONAL TRANSITION; DRUG CONFORMATION; DRUG PROTEIN BINDING; DRUG SYNTHESIS; ENZYME SUBSTRATE; IC 50; STRUCTURE ACTIVITY RELATION;

4-AMINOBENZOIC ACID; AMINO ACIDS; AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ENDOPEPTIDASES; CELL LINE; ENDOPEPTIDASES; ENZYME INHIBITORS; FLUORESCENCE RESONANCE ENERGY TRANSFER; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, MOLECULAR; MOLECULAR MIMICRY; PEPTIDES; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 2942615456     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.04.068     Document Type: Article

References (19)

1. For recent reviews on BACE 1, see: Varghese J., Beck J.P., Bienkowski M.J., Sinha S., Heinrikson R.L. J. Med. Chem. 46:2003;4625
2. Vassar R. Adv. Drug Deliv. Rev. 54:2002;1589
3. Vassar R. J. Mol. Neurosci. 17:2001;157
4. Ghosk A.K., Hong L. Curr. Med. Chem. 9:2002;1135
5. Roggo S. Curr. Top. Med. Chem. 2:2002;359
6. For recent papers on statine-containing BACE 1 inhibitors see: Tung J.S., Davis D.L., Anderson J.P., Walker D.E., Mamo S., Jewett N., Hom R.K., Sinha S., Thorsett E.D., John V. J. Med. Chem. 45:2002;259
7. Hu J., Cwi C.L., Smiley D.L., Timm D., Erickson J.A., McGee J.E., Yang H., Mendel D., May C.P., Shapiro M., McCarthy J.R. Bioorg. Med. Chem. Lett. 13:2003;4335
8. Hom R.K., Fang L.Y., Mamo S., Tung J.S., Guinn A.C., Walker D.E., Davis D.L., Gailunas A.F., Thorsett E.D., Sinha S., Knops J.E., Jewett N.E., Anderson J.P., John V. J. Med. Chem. 46:2003;1799
9. Ghosh A.K., Bilcer G., Harwood C., Kawahama R., Shin D., Hussain K.A., Hong L., Loy J.A., Nguyen C., Koelsch G., Ermolieff J., Tang J. J. Med. Chem. 44:2001;2865
10. John, V.; Tung, J.; Fang, L.; Mamo, S. S. WO 0077030, 2000; Chem. Abstr. 2000, 134, 56968
11. Bridges, K.; Chopra, R.; Lin, L.; Svenson, K.; Tam, A.; Jin, G.; Cowling, R.; Lovering, L.; Akopian, L. N.; Bard, J.; Elizabeth, D.; Bethany, A.; Edward, R. L.; Tod, H. M.; Richard, S. Z.; William, S. S.; Mark, L. S.; Ronald, W. K., unpublished results
12. For molecular modeling studies on BACE 1, see: Tounge B.A., Reynolds C.H. J. Med. Chem. 46:2003;2074
13. For molecular modeling studies on BACE 1, see: (a) Tounge, B. A.; Reynolds, C. H. J. Med. Chem. 2003, 46, 2074; (b) Fan, K. Y.; Hu, B.; Cole, D.; Bridges, K.; Chopra, R.; Manas, E. S.; Katz, A.; Alvarez, J. C.; Lovering, F. E.; Zhou, P.; Jin, G.; Cowling, R.; Bard, J. Abstracts of Papers, 226th ACS National Meeting, New York, NY, United States, September 7-11, 2003, COMP-134
14. For a preliminary account of SARs on bis-statine derivatives, see: Hu, B.; Fan, K.; Bridges, K.; Cole, D.; Zhou, P.; Ellingboe, J.; Jin, G.; Cowling, R.; Bard, J. Abstracts, 58th Northwest Regional Meeting of the American Chemical Society, Bozeman, MT, United States, June 12-14, 2003, 171
15. 1H NMR, mass spectrometry, and high-resolution mass spectrometry or CHN analysis
16. BACE 1 inhibition was measured using recombinant enzyme produced from mammalian expression as described similarly in Ref. [2a]. Fluorogenic substrate Abz-SEVNL-DAEFR-DPa was used with 10 nM human BACE 1 in 0.05 M Na-acetate + 0.05% CHAPS and 25% PBS, pH 4.5 at room temperature. The excitation wavelength was 354 nm, and the emission wavelength was 280 nm. Details of this assay will be described shortly
17. Mcmartin C., Bohacek R.S. J. Comp.-Aided Mol. Des. 11:1997;333
18. Halgren T.A. J. Comp. Chem. 17:1996;616. and the references cited therein
19. Drug Discovery Software SYBYL 6.7 developed by Tripos, St. Louis, USA