title: Diamide amino-imidazoles: a novel series of γ-secretase inhibitors for the treatment of Alzheimer's disease.
abstract: The synthesis and structure-activity relationship (SAR) of a novel series of di-substituted imidazoles, derived from modification of DAPT, are described. Subsequent optimization led to identification of a highly potent series of inhibitors that contain a β-amine in the imidazole side-chain resulting in a robust in vivo reduction of plasma and brain Aβ in guinea pigs. The therapeutic index between Aβ reductions and changes in B-cell populations were studied for compound 10 h.
authors.affiliation: Neuroscience Medicinal Chemistry, Pfizer Global 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: Jeffrey W
authors.initials: JW
authors.lastname: Van Deusen
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Wood
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wood
mesh_terms: D000544:Alzheimer Disease; D000586:Amination / Q000187:drug effects; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D003958:Diamide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D003958:Diamide; C029899:imidazole; D053829:Amyloid Precursor Protein Secretases