Metabolism-Directed Design of Oxetane-Containing Arylsulfonamide Derivatives as 纬-Secretase Inhibitors
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- 作者：Antonia F. Stepan ; Kapil Karki ; W. Scott McDonald ; Peter H. Dorff ; Jason K. Dutra ; Kenneth J. DiRico ; Annie Won ; Chakrapani Subramanyam ; Ivan V. Efremov ; Christopher J. O鈥橠onnell ; Charles E. Nolan ; Stacey L. Becker ; Leslie R. Pustilnik ; Blossom Sneed ; Hao Sun ; Yasong Lu ; Ashley E. Robshaw ; David Riddell ; Theresa J. O'Sullivan ; Evelyn Sibley ; Steven Capetta ; Kevin Atchison ; Andrew J. Hallgren ; Emily Miller ; Anthony Wood ; R. Scott Obach
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：November 24, 2011
- 年：2011
- 卷：54
- 期：22
- 页码：7772-7783
- 全文大小：493K
- 年卷期：v.54,no.22(November 24, 2011)
- ISSN：1520-4804
文摘
A metabolism-based approach toward the optimization of a series of N-arylsulfonamide-based 纬-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鈥揳ctivity 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 纬-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 A尾 in vivo. As such, the study also illustrates the improvement in druglikeness of molecules through the use of the oxetane motif.