title: Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability.
abstract: Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp(3)-character. The lead compound 21 (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain Aβ42 and Aβ40 were observed in a guinea pig time-course experiment.
authors.affiliation: Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Pettersson
authors.affiliation: Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Humphrey
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Butler
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Am Ende
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fish
authors.affiliation: Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Green
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Mullins
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Antonia F
authors.initials: AF
authors.lastname: Stepan
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Stiff
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Tuan P
authors.initials: TP
authors.lastname: Tran
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Beth Cooper
authors.initials: BC
authors.lastname: Vetelino
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Eddie
authors.initials: E
authors.lastname: Yang
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Longfei
authors.initials: L
authors.lastname: Xie
authors.affiliation: Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Bales
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Pustilnik
authors.affiliation: Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Stefanus J
authors.initials: SJ
authors.lastname: Steyn
authors.affiliation: Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wood
authors.affiliation: Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
keywords: Alzheimer’s disease; LipMetE; fluorine; gamma secretase modulators; lipophilic metabolism efficiency