부산대학교 도서관

A metabolism-based approach toward the optimization ofa seriesof N-arylsulfonamide-based γ-secretase inhibitorsis reported. The lead cyclohexyl analogue 6sufferedfrom extensive oxidation on the cycloalkyl motif by cytochrome P4503A4, translating into poor human liver microsomal stability. Knowledgeof the metabolic pathways of 6triggered a structure–activityrelationship study aimed at lowering lipophilicity through the introductionof polarity. This effort led to several tetrahydropyran and tetrahydrofurananalogues, wherein the 3- and 4-substituted variants exhibited greatermicrosomal stability relative to their 2-substituted counterparts.Further reduction in lipophilicity led to the potent γ-secretaseinhibitor and 3-substituted oxetane 1with a reducedpropensity toward oxidative metabolism, relative to its 2-substitutedisomer. The slower rates of metabolism with 3-substituted cyclic ethersmost likely originate from reductions in lipophilicity and/or unfavorableCYP active site interactions with the heteroatom. Preliminary animalpharmacology studies with a representative oxetane indicate that theseries is generally capable of lowering Aβ in vivo. As such,the study also illustrates the improvement in druglikeness of moleculesthrough the use of the oxetane motif. [ABSTRACT FROM AUTHOR]