Piperazinyl pyrimidine derivatives as potent gamma-secretase modulators

Alexey Rivkin; Sean P Ahearn; Stephanie M Chichetti; Yoona R Kim; Chaomin Li; Andrew Rosenau; Sam D Kattar; Joon Jung; Sanjiv Shah; Bethany L Hughes; Jamie L Crispino; Richard E Middleton; Alexander A Szewczak; Benito Munoz; Mark S Shearman

doi:10.1016/j.bmcl.2009.11.101

Piperazinyl pyrimidine derivatives as potent gamma-secretase modulators

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1269-71. doi: 10.1016/j.bmcl.2009.11.101. Epub 2009 Nov 23.

Authors

Alexey Rivkin¹, Sean P Ahearn, Stephanie M Chichetti, Yoona R Kim, Chaomin Li, Andrew Rosenau, Sam D Kattar, Joon Jung, Sanjiv Shah, Bethany L Hughes, Jamie L Crispino, Richard E Middleton, Alexander A Szewczak, Benito Munoz, Mark S Shearman

Affiliation

¹ Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. [email protected]

PMID: 20022243
DOI: 10.1016/j.bmcl.2009.11.101

Abstract

The development of a novel series of piperazinyl pyrimidines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a screening hit provided a series of potent gamma-secretase modulators with >180-fold in vitro selectivity over inhibition of Notch cleavage.

Publication types

Comparative Study

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors
Amyloid Precursor Protein Secretases / metabolism*
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Amyloid beta-Peptides / physiology
Cell Line, Tumor
HeLa Cells
Humans
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism
Piperazines / chemistry*
Piperazines / pharmacology
Pyrimidines / chemistry*
Pyrimidines / pharmacology

Substances

Amyloid beta-Peptides
Peptide Fragments
Piperazines
Pyrimidines
amyloid beta-protein (40-42)
Amyloid Precursor Protein Secretases