title: A-ring modification of SCH 900229 and related chromene sulfone γ-secretase inhibitors.
abstract: Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aβ40-42, compared to their parent compounds.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. wen-lian.wu@merck.com
authors.forename: Wen-Lian
authors.initials: WL
authors.lastname: Wu
authors.forename: Thavalakulamgara K
authors.initials: TK
authors.lastname: Sasikumar
authors.forename: Martin S
authors.initials: MS
authors.lastname: Domalski
authors.forename: Li
authors.initials: L
authors.lastname: Qiang
authors.forename: Duane A
authors.initials: DA
authors.lastname: Burnett
authors.forename: John
authors.initials: J
authors.lastname: Clader
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Tze-Ming
authors.initials: TM
authors.lastname: Chan
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D001578:Benzopyrans; D016227:Benzoquinones; D004791:Enzyme Inhibitors; C581851:SCH 900229; D013450:Sulfones; D005461:Fluorine; C004532:quinone; D053829:Amyloid Precursor Protein Secretases