Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors

This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micro...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-04, Vol.21 (7), p.1942-1947
Hauptverfasser:	Rueeger, Heinrich, Rondeau, Jean-Michel, McCarthy, Clive, Möbitz, Henrik, Tintelnot-Blomley, Marina, Neumann, Ulf, Desrayaud, Sandrine
Format:	Artikel
Sprache:	eng
Schlagworte:	Alzheimer’s disease Amyloid Precursor Protein Secretases - antagonists & inhibitors Aspartic Acid Endopeptidases - antagonists & inhibitors BACE-1 Benzylamines - chemical synthesis Benzylamines - chemistry Benzylamines - pharmacology Biological and medical sciences brain chemistry Crystallography, X-Ray Cyclic S-Oxides - chemical synthesis Cyclic S-Oxides - chemistry Cyclic S-Oxides - pharmacology Cyclization Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology HEA Hydroxyethylamine transition state mimetic Medical sciences Models, Molecular Molecular Structure Neuropharmacology Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Structure-Activity Relationship X-radiation β-Secretase inhibitor
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Zusammenfassung:	This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.02.038