Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE)

• Published in: Bioorganic & medicinal chemistry letters 2015-11, Vol.25 (22), p.5040-5047
• Main Authors: Boy, Kenneth M., Guernon, Jason M., Wu, Yong-Jin, Zhang, Yunhui, Shi, Joe, Zhai, Weixu, Zhu, Shirong, Gerritz, Samuel W., Toyn, Jeremy H., Meredith, Jere E., Barten, Donna M., Burton, Catherine R., Albright, Charles F., Good, Andrew C., Grace, James E., Lentz, Kimberley A., Olson, Richard E., Macor, John E., Thompson, Lorin A.
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid beta-Peptides - biosynthesis; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; BACE; Caco-2 Cells; Cathepsin D - antagonists & inhibitors; Cathepsin E - antagonists & inhibitors; Dogs; Guanidines - chemical synthesis; Guanidines - pharmacology; Humans; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - pharmacology; Madin Darby Canine Kidney Cells; Male; Mice; Molecular Docking Simulation; Pepsin A - antagonists & inhibitors; Proline - analogs & derivatives; Proline - chemical synthesis; Proline - pharmacology; Protease Inhibitors - chemical synthesis; Protease Inhibitors - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.10.031

[Display omitted] The synthesis, evaluation, and structure–activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.