title: Design and synthesis of potent hydroxyethylamine (HEA) BACE-1 inhibitors carrying prime side 4,5,6,7-tetrahydrobenzazole and 4,5,6,7-tetrahydropyridinoazole templates.
abstract: A set of low molecular weight compounds containing a hydroxyethylamine (HEA) core structure with different prime side alkyl substituted 4,5,6,7-tetrahydrobenzazoles and one 4,5,6,7-tetrahydropyridinoazole was synthesized. Striking differences were observed on potencies in the BACE-1 enzymatic and cellular assays depending on the nature of the heteroatoms in the bicyclic ring, from the low active compound 4 to inhibitor 6, displaying BACE-1 IC(50) values of 44 nM (enzyme assay) and 65 nM (cell-based assay).
authors.affiliation: Medivir AB, Lunastigen 7, SE-14144 Huddinge, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Sund
authors.forename: Oscar
authors.initials: O
authors.lastname: Belda
authors.forename: Neera
authors.initials: N
authors.lastname: Borkakoti
authors.forename: Jimmy
authors.initials: J
authors.lastname: Lindberg
authors.forename: Dean
authors.initials: D
authors.lastname: Derbyshire
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
authors.forename: Cathrine
authors.initials: C
authors.lastname: Åhgren
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Woestenenk
authors.forename: Kristina
authors.initials: K
authors.lastname: Wikström
authors.forename: Anders
authors.initials: A
authors.lastname: Eneroth
authors.forename: Erik
authors.initials: E
authors.lastname: Lindström
authors.forename: Genadiy
authors.initials: G
authors.lastname: Kalayanov
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001393:Azoles; D001583:Benzoxazoles; D004791:Enzyme Inhibitors; D005021:Ethylamines; D011725:Pyridines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human