title: Soluble γ-secretase modulators selectively inhibit the production of the 42-amino acid amyloid β peptide variant and augment the production of multiple carboxy-truncated amyloid β species.
abstract: Alzheimer's disease (AD) is characterized pathologically by an abundance of extracellular neuritic plaques composed primarily of the 42-amino acid amyloid β peptide variant (Aβ42). In the majority of familial AD (FAD) cases, e.g., those harboring mutations in presenilin 1 (PS1), there is a relative increase in the levels of Aβ42 compared to the levels of Aβ40. We previously reported the characterization of a series of aminothiazole-bridged aromates termed aryl aminothiazole γ-secretase modulators or AGSMs [Kounnas, M. Z., et al. (2010) Neuron 67, 769-780] and showed their potential for use in the treatment of FAD [Wagner, S. L., et al. (2012) Arch. Neurol. 69, 1255-1258]. Here we describe a series of GSMs with physicochemical properties improved compared to those of AGSMs. Specific heterocycle replacements of the phenyl rings in AGSMs provided potent molecules with improved aqueous solubilities. A number of these soluble γ-secretase modulators (SGSMs) potently lowered Aβ42 levels without inhibiting proteolysis of Notch or causing accumulation of amyloid precursor protein carboxy-terminal fragments, even at concentrations approximately 1000-fold greater than their IC50 values for reducing Aβ42 levels. The effects of one potent SGSM on Aβ peptide production were verified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, showing enhanced production of a number of carboxy-truncated Aβ species. This SGSM also inhibited Aβ42 peptide production in a highly purified reconstituted γ-secretase in vitro assay system and retained the ability to modulate γ-secretase-mediated proteolysis in a stably transfected cell culture model overexpressing a human PS1 mutation validating the potential for use in FAD.
authors.affiliation: Department of Neurosciences, University of California, San Diego , La Jolla, California 92093-0624, United States.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
authors.forename: Soan
authors.initials: S
authors.lastname: Cheng
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Xulun
authors.initials: X
authors.lastname: Zhang
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Rynearson
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Yueming
authors.initials: Y
authors.lastname: Li
authors.forename: Sangram S
authors.initials: SS
authors.lastname: Sisodia
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D057075:Enzyme Assays; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009154:Mutation; D010446:Peptide Fragments / Q000096:biosynthesis*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D051881:Receptor, Notch1 / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D001555:Benzene Derivatives; D007093:Imidazoles; D010446:Peptide Fragments; D053764:Presenilin-1; D051881:Receptor, Notch1; D013844:Thiazoles; C078639:amyloid beta-protein (1-38); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases