Application of Fragment Screening by X-ray Crystallography to the Discovery of Aminopyridines as Inhibitors of β-Secretase

• Published in: Journal of medicinal chemistry Vol. 50; no. 6; pp. 1124 - 1132
• Main Authors: Congreve, Miles, Aharony, David, Albert, Jeffrey, Callaghan, Owen, Campbell, James, Carr, Robin A. E, Chessari, Gianni, Cowan, Suzanna, Edwards, Philip D, Frederickson, Martyn, McMenamin, Rachel, Murray, Christopher W, Patel, Sahil, Wallis, Nicola
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.03.2007; Amer Chemical Soc
• Subjects: Aminoquinolines - chemical synthesis; Aminoquinolines - chemistry; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - chemistry; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Binding Sites; Biological and medical sciences; Chemistry, Medicinal; Crystallography, X-Ray; Humans; Indoles - chemical synthesis; Indoles - chemistry; Life Sciences & Biomedicine; Ligands; Medical sciences; Models, Molecular; Neuropharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Quantitative Structure-Activity Relationship; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; Science & Technology; COMPLEX; DOCKING; PEPTIDOMIMETIC INHIBITORS; AMYLOID PRECURSOR PROTEIN; SUBSTITUTED PIPERIDINES; IDENTIFICATION; POTENT INHIBITORS; STRUCTURE-BASED DESIGN; RENIN INHIBITORS; BACE; Molecular structure; Enzyme; Active site; Enzyme inhibitor; Non peptide compound; X ray diffraction; In vitro; Modeling; Biological activity; Amyloid precursor protein; Pyridine derivatives; Peptidases; Screening; Molecular model; Binding mode; β-secretase; Hydrolases; Aspartic endopeptidases; Indole derivatives; Chemical synthesis; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061197u

Fragment-based lead discovery has been successfully applied to the aspartyl protease enzyme β-secretase (BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acid residues in the active site of the enzyme were the chemical starting points. Structure-based design approaches have led to identification of low micromolar lead compounds that retain these interactions and additionally occupy adjacent hydrophobic pockets of the active site. These leads form two subseries, for which compounds 4 (IC50 = 25 μM) and 6c (IC50 = 24 μM) are representative. In the latter series, further optimization has led to 8a (IC50 = 690 nM).