Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Bioorg Med Chem Lett ; 23(16): 4674-9, 2013 Aug 15.
Article in English | MEDLINE | ID: mdl-23856050

ABSTRACT

The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Chromans/chemistry , Drug Design , Enzyme Inhibitors/chemical synthesis , Binding Sites , Cells, Cultured , Ethylamines/chemical synthesis , Ethylamines/chemistry , Ethylamines/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 20(20): 6034-9, 2010 Oct 15.
Article in English | MEDLINE | ID: mdl-20822903
3.
J Med Chem ; 47(1): 158-64, 2004 Jan 01.
Article in English | MEDLINE | ID: mdl-14695829

ABSTRACT

The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC(50) = 30 nM) toward BACE. Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.


Subject(s)
Amides/chemical synthesis , Aspartic Acid Endopeptidases/chemistry , Dipeptides/chemistry , Ethylenes/chemical synthesis , Phthalic Acids/chemical synthesis , Protease Inhibitors/chemical synthesis , Amides/chemistry , Amyloid Precursor Protein Secretases , Drug Design , Endopeptidases , Ethylenes/chemistry , Humans , Models, Molecular , Molecular Mimicry , Phthalic Acids/chemistry , Protease Inhibitors/chemistry , Structure-Activity Relationship
4.
J Med Chem ; 46(10): 1799-802, 2003 May 08.
Article in English | MEDLINE | ID: mdl-12723942

ABSTRACT

We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.


Subject(s)
Amino Acids/chemical synthesis , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Oligopeptides/chemistry , Amino Acids/chemistry , Amino Acids/pharmacology , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/biosynthesis , Cell Line , Endopeptidases , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Mimicry , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...