SAR of tertiary carbinamine derived BACE1 inhibitors: Role of aspartate ligand amine pK sub(a) in enzyme inhibition

• Published in: Bioorganic & medicinal chemistry letters 2010-03, Vol.20 (6), p.1885-1889
• Main Authors: Rajapakse, Hemaka A, Nantermet, Philippe G, Selnick, Harold G, Barrow, James C, McGaughey, Georgia B, Munshi, Sanjeev, Lindsley, Stacey R, Young, Mary Beth, Ngo, Phung L, Holloway, MKatherine, Lai, Ming-Tain, Espeseth, Amy S, Shi, Xiao-Ping, Colussi, Dennis, Pietrak, Beth, Crouthamel, Ming-Chih, Tugusheva, Katherine, Huang, Qian, Xu, Min, Simon, Adam J, Kuo, Lawrence, Hazuda, Daria J, Graham, Samuel, Vacca, Joseph P
• Format: Article
• Language: English
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.01.137

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 pK sub(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Ab production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5. AB: