Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE)

J Med Chem. 2006 Jul 27;49(15):4544-67. doi: 10.1021/jm060154a.

Abstract

Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa analogues and by alkylation of thiolates or bisthiolates for the others. Molecular modeling suggested that the incorporation of piperidine units appended to the macrocycles improved interactions through additional H-bonds and introduced further rigidity. These were synthesized in enantiomerically pure form using enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was observed with several macroheterocyclic inhibitors and structure-activity relationship (SAR) correlations were deduced. Cocrystal structures of two synthetic analogues revealed interesting and unexpected binding interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Crystallography, X-Ray
  • Endopeptidases / chemistry*
  • Macrocyclic Compounds / chemical synthesis*
  • Macrocyclic Compounds / chemistry
  • Models, Molecular
  • Molecular Mimicry
  • Molecular Structure
  • Oligopeptides / chemistry*
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protein Binding
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Macrocyclic Compounds
  • Oligopeptides
  • Piperidines
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases