Rueeger, Heinrich published the artcileDiscovery 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, Related Products of alcohols-buliding-blocks, the publication is Journal of Medicinal Chemistry (2012), 55(7), 3364-3386, database is CAplus and MEDLINE.
Structure-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 mol. modeling studies and by x-ray anal. 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 physicochem. property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, highly potent compounds were obtained, such as I, with enzymic and cellular IC50 values of 2 and 50 nM, resp., 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.
Journal of Medicinal Chemistry published new progress about 2240-88-2. 2240-88-2 belongs to alcohols-buliding-blocks, auxiliary class Trifluoromethyl,Fluoride,Aliphatic hydrocarbon chain,Alcohol, name is 3,3,3-Trifluoropropan-1-ol, and the molecular formula is C3H5F3O, Related Products of alcohols-buliding-blocks.
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