Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core.
We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxylethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the P1-position. The final inhibitors were optimized using three different amines to provide the residues in the P2'-P3' position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1'-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-1 assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC(50) value of 3.1 nM.
Wångsell
Fredrik
F
Department of Chemistry, Linköping University, SE-581 83 Linköping, Sweden.
Gustafsson
Karin
K
Kvarnström
Ingemar
I
Borkakoti
Neera
N
Edlund
Michael
M
Jansson
Katarina
K
Lindberg
Jimmy
J
Hallberg
Anders
A
Rosenquist
Asa
A
Samuelsson
Bertil
B
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005030:Ethylenes / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D005030:Ethylenes; C067254:hydroxyethylene; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human