Synthesis and biological evaluation of phosphino dipeptide isostere inhibitor of human beta-secretase (BACE1).
Phosphino dipeptide (PDP) isosteres are known to be useful analogues of the transition state of metalloprotease substrates. Here we describe the use of this unit for the design of aspartic protease inhibitors. A PDP analogue of OM00-3, a potent BACE1 inhibitor, was synthesized and exhibited high biological activity (IC50 approximately 12 nM).
Manzenrieder
Florian
F
Department Chemie, Lehrstuhl II für Organische Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
Frank
Andreas O
AO
Huber
Timo
T
Dorner-Ciossek
Cornelia
C
Kessler
Horst
H
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry
D004151:Dipeptides; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human