Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1

Shawn J Stachel; Craig A Coburn; Diane Rush; Kristen L G Jones; Hong Zhu; Hemaka Rajapakse; Samuel L Graham; Adam Simon; M Katharine Holloway; Tim J Allison; Sanjeev K Munshi; Amy S Espeseth; Paul Zuck; Dennis Colussi; Abigail Wolfe; Beth L Pietrak; Ming-Tain Lai; Joseph P Vacca

doi:10.1016/j.bmcl.2009.04.033

Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1

Bioorg Med Chem Lett. 2009 Jun 1;19(11):2977-80. doi: 10.1016/j.bmcl.2009.04.033. Epub 2009 Apr 18.

Authors

Shawn J Stachel¹, Craig A Coburn, Diane Rush, Kristen L G Jones, Hong Zhu, Hemaka Rajapakse, Samuel L Graham, Adam Simon, M Katharine Holloway, Tim J Allison, Sanjeev K Munshi, Amy S Espeseth, Paul Zuck, Dennis Colussi, Abigail Wolfe, Beth L Pietrak, Ming-Tain Lai, Joseph P Vacca

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co, West Point, PA 19486, USA. shawn_stachel@merck.com

PMID: 19409780
DOI: 10.1016/j.bmcl.2009.04.033

Abstract

We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pK(a) of these inhibitors and the pH of the BACE-1 enzyme binding assay.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Heterocyclic Compounds / chemistry*
Heterocyclic Compounds / pharmacology
Hydrogen-Ion Concentration
Protein Binding
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Heterocyclic Compounds
Amyloid Precursor Protein Secretases