Design and synthesis of statine-containing BACE inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 24; pp. 4335 - 4339
• Main Authors: JINGDAN HU, CWI, Cynthia L, MCCARTHY, James R, SMILEY, David L, TIMM, David, ERICKSON, Jon A, MCGEE, James E, YANG, Hsiu-Chiung, MENDEL, David, MAY, Patrick C, SHAPIRO, Mike
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 15.12.2003
• Subjects: Alzheimer Disease - enzymology; Amino Acid Sequence; Amino Acids - chemistry; Amino Acids - pharmacology; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases - antagonists & inhibitors; Biological and medical sciences; Drug Design; Endopeptidases; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Kinetics; Medical sciences; Models, Molecular; Neuropharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Structure-Activity Relationship; Aminoalcohol; Peptides; Enzyme; Alzheimer disease; Enzyme inhibitor; Inhibitor enzyme complex; X ray diffraction; In vitro; Modeling; Amyloid precursor protein; Pseudopeptide; Peptidases; Hydroxyacid; Structure activity relation; Tetrapeptide; Carboxylic acid; Molecular model; β-secretase; Hydrolases; Benzenic compound; Peptide synthesis; Solid phase; Chemical synthesis; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.09.037

Utilizing structure-based techniques and solid-phase synthesis, statine-based tetrapeptide BACE inhibitors were designed and synthesized using a heptapeptide BACE transition-state mimetic, 1, as the starting point. Structure-activity relationship studies at the P(3), P(2), and P(2)' positions as well as the N-terminal capping group on scaffold 5 led to the discovery of potent inhibitors 27, 32, and 34 (IC(50) <100 nM). In addition, computational analysis and the X-ray structure of BACE-inhibitor 38 are discussed.