title: Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: discovery of PF-3084014.
abstract: A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aβ in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aβ EC(50) lead to the identification of compound 14f (PF-3084014) which was selected for clinical development.
authors.affiliation: Neuroscience Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Eastern Point Road, Groton, CT 06340, USA. michael.a.brodney@pfizer.com
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
authors.forename: David D
authors.initials: DD
authors.lastname: Auperin
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Becker
authors.forename: Brian S
authors.initials: BS
authors.lastname: Bronk
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Brown
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Coffman
authors.forename: James E
authors.initials: JE
authors.lastname: Finley
authors.forename: Carol D
authors.initials: CD
authors.lastname: Hicks
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Karmilowicz
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Lanz
authors.forename: Dane
authors.initials: D
authors.lastname: Liston
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.forename: Barbara-Anne
authors.initials: BA
authors.lastname: Martin
authors.forename: Robert B
authors.initials: RB
authors.lastname: Nelson
authors.forename: Charles E
authors.initials: CE
authors.lastname: Nolan
authors.forename: Christine E
authors.initials: CE
authors.lastname: Oborski
authors.forename: Christine P
authors.initials: CP
authors.lastname: Parker
authors.forename: Karl E G
authors.initials: KE
authors.lastname: Richter
authors.forename: Nikolay
authors.initials: N
authors.lastname: Pozdnyakov
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Sahagan
authors.forename: Joel B
authors.initials: JB
authors.lastname: Schachter
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Sokolowski
authors.forename: Barbara
authors.initials: B
authors.lastname: Tate
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Wood
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wood
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Van Deusen
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001681:Biological Assay; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D013764:Tetrahydronaphthalenes; D053829:Amyloid Precursor Protein Secretases; C095210:tetralin; D014633:Valine; C550722:nirogacestat