ABSTRACT
A series of (N-benzyl-N-phenylsulfonamido)alkyl amides were developed from classic and parallel synthesis strategies. Compounds with good in vitro and in vivo γ-secretase activity were identified and described.
Subject(s)
Amides/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Protease Inhibitors/chemistry , Sulfonamides/chemistry , Amides/chemical synthesis , Amides/metabolism , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Peptide Fragments/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Protein Binding , Structure-Activity RelationshipABSTRACT
The synthesis and gamma-secretase inhibition data for a series of carbamate-appended N-alkylsulfonamides are described. Carbamate 54 was found to significantly reduce brain Abeta in transgenic mice. 54 was also found to possess markedly improved brain levels in transgenic mice compared to previously disclosed 1 and 2.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Carbamates/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Brain/drug effects , Brain/metabolism , Mice , Mice, Transgenic , Structure-Activity RelationshipABSTRACT
The synthesis and gamma-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11-47) are described. Inhibition of brain Abeta in transgenic mice was demonstrated by two of these compounds (23 and 44).
Subject(s)
Amines/chemistry , Amines/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Alkylation , Amines/chemical synthesis , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Animals , Azoles/chemical synthesis , Azoles/chemistry , Azoles/pharmacology , Brain/drug effects , Brain/enzymology , Brain/metabolism , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Mice , Mice, Transgenic , Peptide Fragments/metabolism , Protease Inhibitors/chemical synthesis , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
A series of amino-caprolactam sulfonamides were developed from a screening hit. Compounds with good in vitro and in vivo gamma-secretase activity are reported.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Caprolactam/pharmacology , Enzyme Inhibitors/pharmacology , Caprolactam/chemistry , Enzyme Inhibitors/chemistryABSTRACT
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Brain/drug effects , Brain/metabolism , Mice , Mice, Transgenic , Molecular Structure , Protein BindingABSTRACT
We report on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to Abeta reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses.
Subject(s)
Alanine/analogs & derivatives , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Benzodiazepinones/pharmacology , Enzyme Inhibitors/pharmacology , Alanine/pharmacology , Alzheimer Disease/metabolism , Amyloid beta-Peptides , Animals , Mice , Mice, Transgenic , Models, MolecularABSTRACT
2,3-Benzodiazepin-1,4-diones were designed as peptidomimetics at the carboxy terminus of hydroxyamides. Inhibition of brain Abeta production was improved by one of the compounds containing constrained modification.
Subject(s)
Brain/drug effects , Endopeptidases/metabolism , Protease Inhibitors/pharmacology , Alzheimer Disease/enzymology , Amides/chemistry , Amyloid Precursor Protein Secretases , Animals , Aspartic Acid Endopeptidases , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Brain/metabolism , Cell Line , Drug Design , Inhibitory Concentration 50 , Ketones/chemical synthesis , Ketones/pharmacology , Mice , Molecular Conformation , Molecular Mimicry , Protease Inhibitors/chemical synthesis , Protein BindingABSTRACT
Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.
