title: Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors.
abstract: 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.
authors: Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States. Antonia.Stepan@pfizer.com
authors: Antonia F
authors: AF
authors: Stepan
authors: Kapil
authors: K
authors: Karki
authors: W Scott
authors: WS
authors: McDonald
authors: Peter H
authors: PH
authors: Dorff
authors: Jason K
authors: JK
authors: Dutra
authors: Kenneth J
authors: KJ
authors: Dirico
authors: Annie
authors: A
authors: Won
authors: Chakrapani
authors: C
authors: Subramanyam
authors: Ivan V
authors: IV
authors: Efremov
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Charles E
authors: CE
authors: Nolan
authors: Stacey L
authors: SL
authors: Becker
authors: Leslie R
authors: LR
authors: Pustilnik
authors: Blossom
authors: B
authors: Sneed
authors: Hao
authors: H
authors: Sun
authors: Yasong
authors: Y
authors: Lu
authors: Ashley E
authors: AE
authors: Robshaw
authors: David
authors: D
authors: Riddell
authors: Theresa J
authors: TJ
authors: O'Sullivan
authors: Evelyn
authors: E
authors: Sibley
authors: Steven
authors: S
authors: Capetta
authors: Kevin
authors: K
authors: Atchison
authors: Andrew J
authors: AJ
authors: Hallgren
authors: Emily
authors: E
authors: Miller
authors: Anthony
authors: A
authors: Wood
authors: R Scott
authors: RS
authors: Obach
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D051880:Receptors, Notch / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D016229:Amyloid beta-Peptides; D004988:Ethers, Cyclic; D051880:Receptors, Notch; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases; C005287:oxetane