Application of Fragment-Based Lead Generation to the Discovery of Novel, Cyclic Amidine β-Secretase Inhibitors with Nanomolar Potency, Cellular Activity, and High Ligand Efficiency

• Published in: Journal of medicinal chemistry 2007-11, Vol.50 (24), p.5912-5925
• Main Authors: Edwards, Philip D, Albert, Jeffrey S, Sylvester, Mark, Aharony, David, Andisik, Donald, Callaghan, Owen, Campbell, James B, Carr, Robin A, Chessari, Gianni, Congreve, Miles, Frederickson, Martyn, Folmer, Rutger H. A, Geschwindner, Stefan, Koether, Gerard, Kolmodin, Karin, Krumrine, Jennifer, Mauger, Russell C, Murray, Christopher W, Olsson, Lise-Lotte, Patel, Sahil, Spear, Nate, Tian, Gaochao
• Format: Article
• Language: English
• Subjects: Amidines - chemical synthesis; Amidines - chemistry; Amidines - pharmacology; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - chemistry; Amyloid Precursor Protein Secretases - genetics; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - genetics; Biological and medical sciences; Cell Line; Crystallography, X-Ray; Cytosine - analogs & derivatives; Cytosine - chemical synthesis; Cytosine - chemistry; Cytosine - pharmacology; Fluorescence Resonance Energy Transfer; Humans; Ligands; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; 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; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070829p

Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of β-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.