Abstract
Structure-based design and synthesis of a number of potent and selective memapsin 2 inhibitors are described. These inhibitors were designed based upon the X-ray structure of memapsin 2-bound inhibitor 3 that incorporates methylsulfonyl alanine as the P2-ligand and a substituted pyrazole as the P3-ligand. Of particular importance, we examined the ability of the substituted isophthalic acid amide derivative to mimic the key interactions in the S2-S3 regions of the enzyme active sites of 3-bound memapsin 2. We investigated various substituted phenylethyl, alpha-methylbenzyl, and oxazolylmethyl groups as the P3-ligands. A number of inhibitors exhibited very potent inhibitory activity against mempasin 2 and good selectivity against memapsin 1. Inhibitor 5d has shown low nanomolar enzyme inhibitory potency (Ki=1.1 nM) and very good cellular inhibitory activity (IC50=39 nM). Furthermore, in a preliminary study, inhibitor 5d has shown 30% reduction of Abeta40 production in transgenic mice after a single intraperitoneal administration (8 mg/kg). A protein-ligand X-ray crystal structure of 5d-bound memapsin 2 provided vital molecular insight that can serve as an important guide to further design of novel inhibitors.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / chemistry
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / biosynthesis
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / chemistry
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Binding Sites
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CHO Cells
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Cricetinae
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Cricetulus
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Crystallography, X-Ray
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Dipeptides / chemistry
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Drug Design
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Female
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Ligands
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Mice
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Mice, Transgenic
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Models, Molecular
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Molecular Structure
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / biosynthesis
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Phthalic Acids / chemical synthesis*
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Phthalic Acids / chemistry
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Phthalic Acids / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Valine / analogs & derivatives*
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Valine / chemical synthesis
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Valine / chemistry
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Valine / pharmacology
Substances
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Amides
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Amyloid beta-Peptides
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Dipeptides
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GRL 7234
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Ligands
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Peptide Fragments
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Phthalic Acids
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Sulfonamides
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amyloid beta-protein (1-40)
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leucyl-alanine
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse
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Valine