ABSTRACT
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.
Subject(s)
Pteridines/chemistry , Pyrazines/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Half-Life , Pteridines/chemical synthesis , Pteridines/pharmacokinetics , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Structure-Activity RelationshipABSTRACT
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.
