Preorganization of the Hydroxyethylene Dipeptide Isostere:  The Preferred Conformation in Solution Resembles the Conformation Bound to BACE

• Published in: Journal of medicinal chemistry 2005-12, Vol.48 (24), p.7623-7627
• Main Authors: Vidal, Paloma, Timm, David, Broughton, Howard, Chen, Shu-Hui, Martín, José A, Rivera-Sagredo, Alfonso, McCarthy, James R, Shapiro, Michael J, Espinosa, Juan F
• Format: Article
• Language: English
• Subjects: Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Biological and medical sciences; Crystallography, X-Ray; Dipeptides - chemistry; Endopeptidases - chemistry; Humans; Leucine - chemistry; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Molecular Conformation; Neuropharmacology; Pharmacology. Drug treatments; Phenylalanine - chemistry; Protease Inhibitors - chemistry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Solutions; Valine - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050631+

Conformational analysis in solution of β-secretase inhibitors 1 and 2 by NMR spectroscopy reveals that the hydroxyethylene isostere, an apparently flexible fragment widely used as a scissile bond replacement in aspartic protease inhibitors, exists in one predominant conformation in solution. This preferred conformation is similar to that adopted by the hydroxyethylene core of 1 in complex with β-secretase and that adopted by hydroxyethylene cores of related compounds when bound to aspartic proteases, indicating that this structural unit is preorganized in solution.