Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.
Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modification introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.
Department of Chemistry, Linköping University, S-58183 Linköping, Sweden.
Marcus
M
Bäck
Jonas
J
Nyhlén
Ingemar
I
Kvarnström
Sara
S
Appelgren
Neera
N
Borkakoti
Katarina
K
Jansson
Jimmy
J
Lindberg
Susanne
S
Nyström
Anders
A
Hallberg
Sa
S
Rosenquist
Bertil
B
Samuelsson
D000596:Amino Acids / Q000737:chemistry*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D010446:Peptide Fragments; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C013165:statine