Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE)
[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 b...
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Published in | Bioorganic & medicinal chemistry letters Vol. 25; no. 22; pp. 5040 - 5047 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
OXFORD
Elsevier Ltd
15.11.2015
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | [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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0960-894X 1464-3405 |
DOI: | 10.1016/j.bmcl.2015.10.031 |