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 Aß40-42, compared to their parent compounds.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Benzopyrans/chemistry , Enzyme Inhibitors/chemistry , Sulfones/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Benzoquinones/chemical synthesis , Benzoquinones/chemistry , Benzoquinones/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Fluorine/chemistry , Fluorine/pharmacology , Humans , Molecular Structure , Oxidation-Reduction , Sulfones/chemical synthesis , Sulfones/pharmacologyABSTRACT
Isosteric replacement of the urea group of lead compound 1 led to novel substituted piperidine phenylamide analogues. SAR on the electron-induced effects of various linkers as well as substituents on the phenyl rings and the piperidine nitrogen has been investigated. Many single-digit nanomolar MCH R1 antagonists have been identified from this series.
