Aminoimidazoles as BACE-1 inhibitors: The challenge to achieve in vivo brain efficacy

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 5; pp. 1854 - 1859
• Main Authors: Swahn, Britt-Marie, Holenz, Jörg, Kihlström, Jacob, Kolmodin, Karin, Lindström, Johan, Plobeck, Niklas, Rotticci, Didier, Sehgelmeble, Fernando, Sundström, Marie, Berg, Stefan von, Fälting, Johanna, Georgievska, Biljana, Gustavsson, Susanne, Neelissen, Jan, Ek, Margareta, Olsson, Lise-Lotte, Berg, Stefan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.03.2012; Elsevier
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer Disease - metabolism; Alzheimer’s disease (AD); Amines - chemistry; Amines - pharmacokinetics; Amines - pharmacology; Aminoimidazoles; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; BACE-1 inhibitors; beta -Site APP cleaving enzyme 1; Biological and medical sciences; Brain; Brain - drug effects; Brain - enzymology; Brain - metabolism; Cell Line; Crystal structure; Crystallography, X-Ray; Efflux; Hydrogen bonding; Imidazoles - chemistry; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; In vivo brain efficacy; in vivo studies; Medical sciences; Mice; Mice, Inbred C57BL; Models, Molecular; Peptide Fragments - metabolism; Permeability; Pharmacology. Drug treatments; β-Secretase; Efflux; β-Secretase; Alzheimer’s disease (AD); BACE-1 inhibitors; In vivo brain efficacy; Aminoimidazoles; Performance evaluation; Imidazole derivatives; Alzheimer disease; Central nervous system; Alzheimer's disease (AD); β-secretase; Degenerative disease; Aspartic endopeptidases; Nervous system diseases; Enzyme; Treatment efficiency; Rodentia; Chemical structure; Enzyme inhibitor; Antialzheimer agent; Amyloid precursor protein; Cerebral disorder; Peptidases; In vivo; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Hydrolases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.01.079

The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compound 14 and compound 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds are discussed as well as the importance of these properties for attaining in vivo brain efficacy. Compound (R)-25 was selected for evaluation in vivo and 1.5h after oral administration of 300μmol/kg and efflux inhibitor GF120918 to wild type mice the brain Aβ40 level was reduced by 17% and the plasma Aβ40 level by 76%. The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compounds 14 and 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds is discussed as well as the importance of these properties for attaining in vivo brain efficacy. Compound (R)-25 was selected for evaluation in vivo in wild type mice and 1.5h after oral co-administration of 300μmol/kg (R)-25 and efflux inhibitor GF120918 the brain Aβ40 level was reduced by 17% and the plasma Aβ40 level by 76%.