title: Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulators.
abstract: Herein we describe the design and synthesis of a novel series of γ-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain Aβ42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the γ-secretase complex, thus gaining insight into the binding site of this series of GSMs.
authors.affiliation: Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Pettersson
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Bales
authors.forename: Christopher W
authors.initials: CW
authors.lastname: am Ende
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fish
authors.forename: Michael E
authors.initials: ME
authors.lastname: Green
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Mullins
authors.forename: Thayalan
authors.initials: T
authors.lastname: Navaratnam
authors.forename: Subas M
authors.initials: SM
authors.lastname: Sakya
authors.forename: Cory M
authors.initials: CM
authors.lastname: Stiff
authors.forename: Tuan P
authors.initials: TP
authors.lastname: Tran
authors.forename: Longfei
authors.initials: L
authors.lastname: Xie
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Pustilnik
authors.forename: Beth C
authors.initials: BC
authors.lastname: Vetelino
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wood
authors.forename: Nikolay
authors.initials: N
authors.lastname: Pozdnyakov
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000737:chemistry; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053764:Presenilin-1; D011724:Pyridazines; D011725:Pyridines; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases