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Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors. 2011
Antonia F Stepan, and
Kapil Karki, and
W Scott McDonald, and
Peter H Dorff, and
Jason K Dutra, and
Kenneth J Dirico, and
Annie Won, and
Chakrapani Subramanyam, and
Ivan V Efremov, and
Christopher J O'Donnell, and
Charles E Nolan, and
Stacey L Becker, and
Leslie R Pustilnik, and
Blossom Sneed, and
Hao Sun, and
Yasong Lu, and
Ashley E Robshaw, and
David Riddell, and
Theresa J O'Sullivan, and
Evelyn Sibley, and
Steven Capetta, and
Kevin Atchison, and
Andrew J Hallgren, and
Emily Miller, and
Anthony Wood, and
R Scott Obach
Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States. Antonia.Stepan@pfizer.com
A metabolism-based approach toward the optimization of a series of N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analogue 6 suffered from extensive oxidation on the cycloalkyl motif by cytochrome P450 3A4, translating into poor human liver microsomal stability. Knowledge of the metabolic pathways of 6 triggered a structure-activity relationship study aimed at lowering lipophilicity through the introduction of polarity. This effort led to several tetrahydropyran and tetrahydrofuran analogues, wherein the 3- and 4-substituted variants exhibited greater microsomal stability relative to their 2-substituted counterparts. Further reduction in lipophilicity led to the potent γ-secretase inhibitor and 3-substituted oxetane 1 with a reduced propensity toward oxidative metabolism, relative to its 2-substituted isomer. The slower rates of metabolism with 3-substituted cyclic ethers most likely originate from reductions in lipophilicity and/or unfavorable CYP active site interactions with the heteroatom. Preliminary animal pharmacology studies with a representative oxetane indicate that the series is generally capable of lowering Aβ in vivo. As such, the study also illustrates the improvement in druglikeness of molecules through the use of the oxetane motif.
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Ivan V Efremov, and
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Hao Sun, and
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Stacey L Becker, and
Leslie R Pustilnik, and
Blossom Sneed, and
Hao Sun, and
Yasong Lu, and
Ashley E Robshaw, and
David Riddell, and
Theresa J O'Sullivan, and
Evelyn Sibley, and
Steven Capetta, and
Kevin Atchison, and
Andrew J Hallgren, and
Emily Miller, and
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Annie Won, and
Chakrapani Subramanyam, and
Ivan V Efremov, and
Christopher J O'Donnell, and
Charles E Nolan, and
Stacey L Becker, and
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Blossom Sneed, and
Hao Sun, and
Yasong Lu, and
Ashley E Robshaw, and
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Steven Capetta, and
Kevin Atchison, and
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R Scott Obach
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Ivan V Efremov, and
Christopher J O'Donnell, and
Charles E Nolan, and
Stacey L Becker, and
Leslie R Pustilnik, and
Blossom Sneed, and
Hao Sun, and
Yasong Lu, and
Ashley E Robshaw, and
David Riddell, and
Theresa J O'Sullivan, and
Evelyn Sibley, and
Steven Capetta, and
Kevin Atchison, and
Andrew J Hallgren, and
Emily Miller, and
Anthony Wood, and
R Scott Obach
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Chakrapani Subramanyam, and
Ivan V Efremov, and
Christopher J O'Donnell, and
Charles E Nolan, and
Stacey L Becker, and
Leslie R Pustilnik, and
Blossom Sneed, and
Hao Sun, and
Yasong Lu, and
Ashley E Robshaw, and
David Riddell, and
Theresa J O'Sullivan, and
Evelyn Sibley, and
Steven Capetta, and
Kevin Atchison, and
Andrew J Hallgren, and
Emily Miller, and
Anthony Wood, and
R Scott Obach
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