Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 1, 2004, Pages 239-243

  Lamar, Jason ^a   Hu, Jingdan ^a   Bueno, Ana Belen ^a   Yang, Hsiu Chiung ^a   Guo, Deqi ^a   Copp, James D ^a   McGee, James ^a   Gitter, Bruce ^a   Timm, David ^a   May, Patrick ^a   McCarthy, James ^a   Chen, Shu Hui ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE; BETA SECRETASE; BETA SECRETASE INHIBITOR; PENTAPEPTIDE; PHENYLALANINE; VALINE; ASPARTIC PROTEINASE; BACE1 PROTEIN, HUMAN; DIPEPTIDE; PHENYLALANYLALANINE; PROTEINASE; PROTEINASE INHIBITOR; SECRETASE;

ARTICLE; CARBOXY TERMINAL SEQUENCE; CELL ACTIVITY; CHEMICAL MODIFICATION; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYTOTOXICITY; DRUG EFFECT; DRUG POTENCY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; EMBRYO; ENZYME INHIBITION; HUMAN; HUMAN CELL; IC 50; MASS SPECTROMETRY; PROTON NUCLEAR MAGNETIC RESONANCE; STRUCTURE ACTIVITY RELATION; CELL LINE; METABOLISM; MOLECULAR MIMICRY; SYNTHESIS;

AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ENDOPEPTIDASES; CELL LINE; DIPEPTIDES; ENDOPEPTIDASES; HUMANS; MOLECULAR MIMICRY; PROTEASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0346256828     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2003.09.084     Document Type: Article

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25. This amino acid was prepared according to the following route: .
26. This amino acid was synthesized via five-step sequence shown below: .
27. N-Boc protected diFluoroAbu was prepared according to the following sequence: .
28. BACE FRET assay uses 20 nM purified recombinant human BACE/Fc. The standard assay format contains 100 μM ELGY-9 (an aminobenzoate based FRET peptide containing Swedish mutation) in 50 mM ammonium acetate, pH 4.6, 1 mg/mL BSA and 1 mM Triton X-100 at room temperature for 4 h. The enzyme activity is determined by an increase in the relative fluorescent of reaction mixture, with umbilliferone excitation/emission filter set.
29. 2. The conditioned media are removed from the culture wells. The Aβ ELISA is used to measure amount of Aβ(total) peptide produced during the incubation time.
30. 35 is counted.
31. free=0.222) using CNX (Accelrys, Inc).
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