title: Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin.
abstract: Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aβ42 was achieved in a rat efficacy model when dosed orally at 30mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex.
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA. Electronic address: martin.pettersson@pfizer.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Pettersson
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.affiliation: Eastern Point Road, Groton, CT 06340, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Humphrey
authors.affiliation: Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Am Ende
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Edelweiss
authors.initials: E
authors.lastname: Evrard
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Efremov
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Antonia F
authors.initials: AF
authors.lastname: Stepan
authors.affiliation: Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Stiff
authors.affiliation: Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Longfei
authors.initials: L
authors.lastname: Xie
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Bales
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Hajos-Korcsok
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Murrey
authors.affiliation: Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Pustilnik
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Stefanus J
authors.initials: SJ
authors.lastname: Steyn
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wood
authors.affiliation: Pfizer Worldwide Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects*; D000818:Animals; D055808:Drug Discovery; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D053763:Presenilins / Q000187:drug effects*; D011719:Pyrazines / Q000737:chemistry*; D051381:Rats
chemical_list: D007211:Indoles; D053763:Presenilins; D011719:Pyrazines; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; γ-Secretase modulators