Discovery of furo[2,3-d][1,3]thiazinamines as beta amyloid cleaving enzyme-1 (BACE1) inhibitors.
This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.
Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: Yong-Jin.Wu@bms.com.
Yong-Jin
YJ
Wu
Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Jason
J
Guernon
Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Ramkumar
R
Rajamani
Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Jeremy H
JH
Toyn
Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Michael K
MK
Ahlijanian
Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Charles F
CF
Albright
Research and Development, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543, USA.
Jodi
J
Muckelbauer
Research and Development, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543, USA.
ChiehYing
C
Chang
Research and Development, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543, USA.
Dan
D
Camac
Research and Development, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543, USA.
John E
JE
Macor
Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Lorin A
LA
Thompson
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D013843:Thiazines / Q000737:chemistry* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005663:Furans; D013843:Thiazines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Alzheimer’s disease; BACE1 inhibitor; Furo[2,3-d][1,3]thiazinamine