title: Optimization of a natural product-based class of γ-secretase modulators.
abstract: A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compounds with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochemical properties of the analogues. This strategy gave compounds with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compounds, 100 and 120, were tested for a pharmacodynamic effect in the strain and lowered brain Aβ42 levels.
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, Massachusetts 02139, United States. jed.hubbs@satoripharma.com
authors.forename: Jed L
authors.initials: JL
authors.lastname: Hubbs
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Fuller
authors.forename: Wesley F
authors.initials: WF
authors.lastname: Austin
authors.forename: Ruichao
authors.initials: R
authors.lastname: Shen
authors.forename: Steffen P
authors.initials: SP
authors.lastname: Creaser
authors.forename: Timothy D
authors.initials: TD
authors.lastname: McKee
authors.forename: Robyn M B
authors.initials: RM
authors.lastname: Loureiro
authors.forename: Barbara
authors.initials: B
authors.lastname: Tate
authors.forename: Weiming
authors.initials: W
authors.lastname: Xia
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ives
authors.forename: Brian S
authors.initials: BS
authors.lastname: Bronk
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001688:Biological Products / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004987:Ethers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010539:Permeability; D051381:Rats; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D001688:Biological Products; D002219:Carbamates; D004987:Ethers; D010446:Peptide Fragments; D014315:Triterpenes; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases