title: Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human beta-secretase.
abstract: 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.
authors.affiliation: Elan, 800 Gateway Boulevard, South San Francisco, California 94080, USA.
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Andrea F
authors.initials: AF
authors.lastname: Gailunas
authors.forename: Shumeye
authors.initials: S
authors.lastname: Mamo
authors.forename: Larry Y
authors.initials: LY
authors.lastname: Fang
authors.forename: Jay S
authors.initials: JS
authors.lastname: Tung
authors.forename: Donald E
authors.initials: DE
authors.lastname: Walker
authors.forename: David
authors.initials: D
authors.lastname: Davis
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Thorsett
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Jewett
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Moon
authors.forename: Varghese
authors.initials: V
authors.lastname: John
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D004151:Dipeptides / Q000737:chemistry*; D015195:Drug Design; D010450:Endopeptidases; D005030:Ethylenes / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D004151:Dipeptides; D005030:Ethylenes; C481784:N-(1-(3,5-difluorobenzyl)-2-hydroxy-4-isobutylcarbamoylpentyl)-N',N'-dipropylisophthalamide; D010795:Phthalic Acids; D011480:Protease Inhibitors; C067254:hydroxyethylene; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human