Stereochemical analysis of (hydroxyethyl)urea peptidomimetic inhibitors of gamma-secretase.
(Hydroxyethyl)urea peptidomimetics systematically altered at positions P2-P3' with hydrophobic D-amino acids were synthesized. An all D-amino acid containing analogue was identified that effectively blocked gamma-secretase activity in a cell-free system (IC50 = 30 nM). Systematic alteration of the stereocenters of a potent compound revealed interdependence between the various positions. Although typically less potent than their L-peptidomimetic counterparts, selected all D-amino acid containing analogues were equipotent to their counterparts in a cell-based assay when incubated for extended times.
Bakshi
Pancham
P
Center for Neurologic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wolfe
Michael S
MS
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D016466:CHO Cells; D002474:Cell-Free System; D006224:Cricetinae; D003412:Cricetulus; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; D016564:Amyloid beta-Protein Precursor; D010455:Peptides; D011480:Protease Inhibitors; D014508:Urea; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human