title: Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine β-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors.
abstract: Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Aβ reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors.
authors: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Yong-Jin
authors: YJ
authors: Wu
authors: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Jason
authors: J
authors: Guernon
authors: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Jianliang
authors: J
authors: Shi
authors: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Lawrence
authors: L
authors: Marcin
authors: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Mendi
authors: M
authors: Higgins
authors: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Ramkumar
authors: R
authors: Rajamani
authors: Research and Development, Bristol-Myers Squibb Company , PO Box 4000, Princeton, New Jersey 08543-4000, United States.
authors: Jodi
authors: J
authors: Muckelbauer
authors: Research and Development, Bristol-Myers Squibb Company , PO Box 4000, Princeton, New Jersey 08543-4000, United States.
authors: Hal
authors: H
authors: Lewis
authors: Research and Development, Bristol-Myers Squibb Company , PO Box 4000, Princeton, New Jersey 08543-4000, United States.
authors: ChiehYing
authors: C
authors: Chang
authors: Research and Development, Bristol-Myers Squibb Company , PO Box 4000, Princeton, New Jersey 08543-4000, United States.
authors: Dan
authors: D
authors: Camac
authors: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Jeremy H
authors: JH
authors: Toyn
authors: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Michael K
authors: MK
authors: Ahlijanian
authors: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Charles F
authors: CF
authors: Albright
authors: Research and Development, Bristol-Myers Squibb Company , PO Box 4000, Princeton, New Jersey 08543-4000, United States.
authors: John E
authors: JE
authors: Macor
authors: Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors: Lorin A
authors: LA
authors: Thompson
mesh_terms: D000586:Amination; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D051381:Rats; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D013843:Thiazines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human