2. Academic Validation
  3. Peptidomimetic β-Secretase Inhibitors Comprising a Sequence of Amyloid-β Peptide for Alzheimer's Disease

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

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.

Figures
Products