Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 7; pp. 2444 - 2449
• Main Authors: Cumming, Jared N., Smith, Elizabeth M., Wang, Lingyan, Misiaszek, Jeffrey, Durkin, James, Pan, Jianping, Iserloh, Ulrich, Wu, Yusheng, Zhu, Zhaoning, Strickland, Corey, Voigt, Johannes, Chen, Xia, Kennedy, Matthew E., Kuvelkar, Reshma, Hyde, Lynn A., Cox, Kathleen, Favreau, Leonard, Czarniecki, Michael F., Greenlee, William J., McKittrick, Brian A., Parker, Eric M., Stamford, Andrew W.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-04-2012; Elsevier
• Subjects: Administration, Oral; Alzheimer Disease - blood; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - drug therapy; Alzheimer′s disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - blood; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Antibodies; Anticonvulsants - chemical synthesis; Anticonvulsants - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; BACE; beta -Site APP cleaving enzyme 1; Binding Sites; Biological and medical sciences; Central nervous system; Computer Simulation; Crystallography, X-Ray; Data processing; Disease Models, Animal; Drug Design; enzyme inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Humans; Hydantoins - chemical synthesis; Hydantoins - pharmacology; Iminohydantoin; In vivo; Medical sciences; Models, Molecular; Oral administration; Pharmacology. Drug treatments; Protein Binding; Rats; Rats, Sprague-Dawley; β-Secretase; In vivo; Alzheimer′s disease; β-Secretase; Iminohydantoin; BACE; Nervous system diseases; Enzyme; Alzheimer disease; Oral administration; Enzyme inhibitor; Antialzheimer agent; Amyloid precursor protein; Cerebral disorder; Peptidases; Structure activity relation; Central nervous system disease; β-secretase; Hydrolases; Degenerative disease; Aspartic endopeptidases; Alzheimer's disease
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.02.013

From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F′ subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.