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1.
Bioorg Med Chem Lett ; 21(19): 5791-4, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21885276

ABSTRACT

The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate ß-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Protein Precursor/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , Inhibitory Concentration 50 , Mice , Mice, Inbred Strains , Structure-Activity Relationship , Sulfonamides/chemistry
3.
Bioorg Med Chem Lett ; 14(7): 1651-4, 2004 Apr 05.
Article in English | MEDLINE | ID: mdl-15026043

ABSTRACT

A pro-drug strategy to identify orally efficacious VLA-4 antagonists is described. Potential pro-drugs were evaluated for their physical chemical characteristics and in vitro properties, including solubility, stability, permeability and plasma stability. Based on this characterization, promising compounds were identified for in vivo pharmacokinetic evaluation. These studies resulted in the identification of a pro-drug that exhibited desirable blood levels in PK studies in several different species.


Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Prodrugs/chemical synthesis , Animals , Drug Evaluation, Preclinical/methods , Integrin alpha4beta1/metabolism , Male , Prodrugs/metabolism , Rats
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