Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human beta-secretase.
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.
Hom
Roy K
RK
Elan, 800 Gateway Boulevard, South San Francisco, California 94080, USA.
Gailunas
Andrea F
AF
Mamo
Shumeye
S
Fang
Larry Y
LY
Tung
Jay S
JS
Walker
Donald E
DE
Davis
David
D
Thorsett
Eugene D
ED
Jewett
Nancy E
NE
Moon
Joseph B
JB
John
Varghese
V
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
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