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SAR of tertiary carbinamine derived BACE1 inhibitors: role of aspartate ligand amine pKa in enzyme inhibition

Authors :
Phung L. Ngo
Harold G. Selnick
Xiao Ping Shi
Dennis Colussi
Beth Pietrak
Sanjeev Munshi
Ming Tain Lai
Min Xu
Georgia B. McGaughey
James C. Barrow
Lawrence Kuo
Philippe G. Nantermet
Adam J. Simon
Mary Beth Young
Daria J. Hazuda
Stacey R. Lindsley
Hemaka A. Rajapakse
Ming-Chih Crouthamel
Amy S. Espeseth
Katherine Tugusheva
Samuel L. Graham
M. Katharine Holloway
Qian Huang
Joseph P. Vacca
Source :
Bioorganicmedicinal chemistry letters. 20(6)
Publication Year :
2010

Abstract

The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pKa of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Αβ production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.

Details

ISSN :
14643405
Volume :
20
Issue :
6
Database :
OpenAIRE
Journal :
Bioorganicmedicinal chemistry letters
Accession number :
edsair.doi.dedup.....1fa021e12b11a8ad9927b76ea326038f