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/chemistryABSTRACT
A series of N-(pyrimidin-4-yl)-phenylalanine VLA-4 antagonists is described. Optimization of substituents at the 2 and 5 positions of the pyrimidine ring gave 14, a very potent VLA-4 inhibitor which is orally active in a sheep asthma model.
Subject(s)
Asthma/drug therapy , Disease Models, Animal , Integrin alpha4beta1/antagonists & inhibitors , Pyrimidines/therapeutic use , Administration, Oral , Animals , Asthma/metabolism , Biological Availability , Drug Discovery , Pyrimidines/pharmacokinetics , SheepABSTRACT
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 , RatsABSTRACT
Potent, small molecule A beta inhibitors have been prepared that incorporate an alanine core bracketed by an N-terminal arylacetyl group and various C-terminal amino alcohols. The compounds exhibit stereospecific inhibition as demonstrated in an in vitro assay.
