Journal of Medicinal Chemistry · 2003 · 80 citations · 10 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryStructure-activity RelationshipsEnzyme InhibitionLead Compound DesignLigand-based DesignPeptidomimetic DesignStructure-activity Relationship AnalysisAromatic Carboxylic AcidsBeta Secretase InhibitionCell Penetration MechanismsInhibitor SelectivityMedicinal Chemistry ApplicationsPeptidomimetic Library SynthesisStructure-based Lead DiscoveryStructure-based Peptidomimetics
The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC(50) = 30 nM) toward BACE. Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.
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