Peptidomimetic β-Secretase Inhibitors Comprising a Sequence of Amyloid-β Peptide for Alzheimer's Disease

  • J Med Chem. 2015 Jul 23;58(14):5408-18. doi: 10.1021/acs.jmedchem.5b00658.
Helder Vila-Real  1  2 ,  Helena Coelho  1  2 ,  João Rocha  3 ,  Adelaide Fernandes  3 ,  M Rita Ventura  2 ,  Christopher D Maycock  2  4 ,  Olga Iranzo  2 ,  Ana L Simplício  1  2
Affiliations
  • 1. †Instituto de Biologia Experimental e Tecnológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.
  • 2. ‡Instituto de Tecnologia Química e Biológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.
  • 3. ∥Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
  • 4. ⊥Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
PMID: 26061085 DOI: 10.1021/acs.jmedchem.5b00658
Abstract

Alzheimer's disease is a grave social problem in an aging population. A major problem is the passage of drugs through the blood-brain barrier. This work tests the hypothesis that the conjugation of peptidomimetic β-secretase inhibitors with a fragment of Amyloid-β peptide facilitates entrance into the central nervous system. HVR-3 (compound 4), one of the conjugation products, was found to be as potent as OM00-3, a known peptidomimetic inhibitor, 4-fold more selective toward β-secretase 1 in relation to β-secretase 2 and 3-fold more resistant to in vitro metabolization in human serum. Its intravenous administration to mice and Wistar rats generated an active metabolite recovered from the rodent's brains.

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