title: Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents.
abstract: By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Guernon
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Fukang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Snyder
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Shi
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mcclure
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Rajamani
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Park
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ng
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , PO Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Hal
authors.initials: H
authors.lastname: Lewis
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , PO Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: ChiehYing
authors.initials: C
authors.lastname: Chang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , PO Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Camac
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Toyn
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Ahlijanian
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , PO Box 4000, Princeton, New Jersey 08543-4000, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Lorin A
authors.initials: LA
authors.lastname: Thompson
keywords: Alzheimer’s disease; Aβ42; BACE1; aminothiazine; amyloid hypothesis; inhibitor