Design and synthesis of BACE-1 inhibitors utilizing a tertiary hydroxyl motif as the transition state mimic.
Two series of drug-like BACE-1 inhibitors with a shielded tertiary hydroxyl as transition state isostere have been synthesized. The most potent inhibitor exhibited a BACE-1 IC(50) value of 0.23 microM.
Wångsell
Fredrik
F
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC, SE-751 23 Uppsala, Sweden.
Russo
Francesco
F
Sävmarker
Jonas
J
Rosenquist
Asa
A
Samuelsson
Bertil
B
Larhed
Mats
M
D000596:Amino Acids / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D002402:Cathepsin D; C013165:statine