Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides
2012; American Chemical Society; Volume: 55; Issue: 7 Linguagem: Inglês
10.1021/jm300069y
ISSN1520-4804
AutoresHeinrich Rueeger, Rainer Lueoend, Olivier Rogel, Jean‐Michel Rondeau, Henrik Möbitz, Rainer Machauer, Laura H. Jacobson, Matthias Staufenbiel, Sandrine Desrayaud, Ulf Neumann,
Tópico(s)Computational Drug Discovery Methods
ResumoStructure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.
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