Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: Structure–activity relationship of P2′ substituents

• Published in: Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (16), p.4789-4794
• Main Authors: Truong, Anh P., Probst, Gary D., Aquino, Jose, Fang, Larry, Brogley, Louis, Sealy, Jennifer M., Hom, Roy K., Tucker, John A., John, Varghese, Tung, Jay S., Pleiss, Michael A., Konradi, Andrei W., Sham, Hing L., Dappen, Michael S., Tóth, Gergley, Yao, Nanhua, Brecht, Eric, Pan, Hu, Artis, Dean R., Ruslim, Lany, Bova, Michael P., Sinha, Sukanto, Yednock, Ted A., Zmolek, Wes, Quinn, Kevin P., Sauer, John-Michael
• Format: Article
• Language: English
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacokinetics; Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; BACE-1 inhibitor; Binding Sites; Biological and medical sciences; Butanols - chemical synthesis; Butanols - chemistry; Butanols - pharmacokinetics; Cell Membrane Permeability - drug effects; Crystallography, X-Ray; Cyclohexylamines - chemical synthesis; Cyclohexylamines - chemistry; Cyclohexylamines - pharmacokinetics; Humans; Hydroxyethylamine (HEA); Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacokinetics; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.06.112

Herein, we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2′ position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay. Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2′ position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.