Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE). Issue 22 (15th November 2015)

• Record Type: Journal Article
• 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 22(2015)
• Page Start: 5040
• Page End: 5047
• Publication Date: 2015-11-15
• Subjects: BACE -- Alzheimer's disease; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.10.031
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 analog21c is presented.