ABSTRACT
With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2' sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Abeta(40) in transgenic mice with a single subcutaneous dose.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Piperazines/chemistry , Protease Inhibitors/chemical synthesis , Sulfonamides/chemistry , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Crystallography, X-Ray , Drug Design , Mice , Mice, Transgenic , Models, Molecular , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Piperazine , Protease Inhibitors/chemistry , Protease Inhibitors/therapeutic use , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/therapeutic useABSTRACT
Structure-activity studies on lead cyclobutenedione 3 led to the discovery of 4 (SCH 527123), a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist with excellent cell-based activity. Compound 4 displayed good oral bioavailability in rat and may be a potential therapeutic agent for the treatment of various inflammatory diseases.
Subject(s)
Benzamides/pharmacology , Cyclobutanes/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemical synthesis , Biological Availability , Cyclobutanes/administration & dosage , Cyclobutanes/chemical synthesis , Molecular Structure , Rats , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of 3,4-diaminocyclobut-3-ene-1,2-diones was prepared and found to show potent inhibitory activity of CXCR2 binding and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Microsome stability and Caco2 studies were subsequently used to show that compounds of this chemotype are predicted to have good oral bioavailability and are thus suitable for pharmaceutical development.
