ABSTRACT
From high throughput screening, we discovered compound 1, the prototype for a series of disubstituted thiophene inhibitors of JNK which is selective towards closely related MAP kinases p38 and Erk2. Herein we describe the evolution of these compounds to a novel class of thiophene and thiazole JNK inhibitors that retain favorable solubility, permeability, and P-gp properties for development as CNS agents for treatment of neurodegeneration. Compound 61 demonstrated JNK3 IC(50)=77 nM and retained the excellent broad kinase selectivity observed for the series.
Subject(s)
JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Quinolines/chemical synthesis , Thiazoles/chemistry , Thiophenes/chemistry , Animals , Drug Design , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Mice , Microsomes, Liver/metabolism , Mitogen-Activated Protein Kinase 10/antagonists & inhibitors , Mitogen-Activated Protein Kinase 10/metabolism , Mitogen-Activated Protein Kinase 8/antagonists & inhibitors , Mitogen-Activated Protein Kinase 8/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2' position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.
Subject(s)
Acetamides/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Butanols/chemistry , Cyclohexylamines/chemistry , Protease Inhibitors/chemistry , Acetamides/chemical synthesis , Acetamides/pharmacokinetics , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Butanols/chemical synthesis , Butanols/pharmacokinetics , Cell Membrane Permeability/drug effects , Crystallography, X-Ray , Cyclohexylamines/chemical synthesis , Cyclohexylamines/pharmacokinetics , Humans , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
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 RelationshipABSTRACT
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.
