title: Peptidomimetic β-Secretase Inhibitors Comprising a Sequence of Amyloid-β Peptide for Alzheimer's Disease.
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.
authors.affiliation: †Instituto de Biologia Experimental e Tecnológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.|‡Instituto de Tecnologia Química e Biológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.
authors.forename: Helder
authors.initials: H
authors.lastname: Vila-Real
authors.affiliation: †Instituto de Biologia Experimental e Tecnológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.|‡Instituto de Tecnologia Química e Biológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Coelho
authors.affiliation: ∥Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Rocha
authors.affiliation: ∥Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Fernandes
authors.affiliation: ‡Instituto de Tecnologia Química e Biológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.
authors.forename: M Rita
authors.initials: MR
authors.lastname: Ventura
authors.affiliation: ‡Instituto de Tecnologia Química e Biológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.|⊥Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Maycock
authors.affiliation: ‡Instituto de Tecnologia Química e Biológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.
authors.forename: Olga
authors.initials: O
authors.lastname: Iranzo
authors.affiliation: †Instituto de Biologia Experimental e Tecnológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.|‡Instituto de Tecnologia Química e Biológica, Av. da República, Quinta do Marquês, 2780-157 Oeiras, Portugal.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Simplício
mesh_terms: D000215:Acylation; D000544:Alzheimer Disease / Q000188:drug therapy*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D057786:Peptidomimetics / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D057786:Peptidomimetics; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases