Design and synthesis of potent and selective BACE-1 inhibitors.
Highly potent BACE-1 protease inhibitors have been developed from an inhibitors containing a hydroxyethylene (HE) core displaying aryloxymethyl or benzyloxymethyl P1 side chain and a methoxy P1' side chain. The target molecules were synthesized in good overall yields from chiral carbohydrate starting materials. The inhibitors show high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnishes BACE-1 K(i) << 1 nM and displays >1000-fold selectivity over cathepsin D.
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.
Catarina
C
Björklund
Stefan
S
Oscarson
Kurt
K
Benkestock
Neera
N
Borkakoti
Katarina
K
Jansson
Jimmy
J
Lindberg
Lotta
L
Vrang
Anders
A
Hallberg
Asa
A
Rosenquist
Bertil
B
Samuelsson
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D018360:Crystallography, X-Ray; D015195:Drug Design; D005030:Ethylenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D005030:Ethylenes; C067254:hydroxyethylene; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D002402:Cathepsin D