title: Investigation of α-phenylnorstatine and α-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors.
abstract: Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and β-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC(50)=0.19μM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wångsell
authors.forename: Patrik
authors.initials: P
authors.lastname: Nordeman
authors.forename: Jonas
authors.initials: J
authors.lastname: Sävmarker
authors.forename: Rikard
authors.initials: R
authors.lastname: Emanuelsson
authors.forename: Katarina
authors.initials: K
authors.lastname: Jansson
authors.forename: Jimmy
authors.initials: J
authors.lastname: Lindberg
authors.forename: Sa
authors.initials: S
authors.lastname: Rosenquist
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010654:Phenylbutyrates; D011480:Protease Inhibitors; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human