Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences
| Autor: | José Francisco Soriano, Javier Agejas, Rosario Gonzalez, Ramón Rodríguez, Timothy B. Durham, Howard Barff Broughton, Juan F. Espinosa, Paloma Vidal, Ana B. Bueno, Robert Dean Dally, Hsiu-Chiung Yang, Alicia Marcos, David E. Timm, Gema Sanz, James R. McCarthy, Patric James Hahn |
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| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular Steric effects Magnetic Resonance Spectroscopy Stereochemistry Isostere Morpholines Peptide Crystallography X-Ray 01 natural sciences Pyrrolidine Mice Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Ethylamines Animals Aspartic Acid Endopeptidases Humans Molecule Protease Inhibitors chemistry.chemical_classification biology 010405 organic chemistry Chemistry Brain Active site 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Cyclization Drug Design biology.protein Molecular Medicine Piperidine Amyloid Precursor Protein Secretases Peptides |
| Zdroj: | Journal of Medicinal Chemistry. 60:9807-9820 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b01304 |
| Popis: | NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors. |
| Databáze: | OpenAIRE |
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