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Bioorg Med Chem Lett. 2015 Nov 15;25(22):5040-7. doi: 10.1016/j.bmcl.2015.10.031. Epub 2015 Oct 20.

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

Author information

1
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: boyk@bms.com.
2
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.

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 analog 21c is presented.

KEYWORDS:

Alzheimer’s disease; BACE

PMID:
26497283
DOI:
10.1016/j.bmcl.2015.10.031
[Indexed for MEDLINE]

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