Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1.
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.
Stachel
Shawn J
SJ
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co, West Point, PA 19486, USA. shawn_stachel@merck.com
Coburn
Craig A
CA
Rush
Diane
D
Jones
Kristen L G
KL
Zhu
Hong
H
Rajapakse
Hemaka
H
Graham
Samuel L
SL
Simon
Adam
A
Katharine Holloway
M
M
Allison
Tim J
TJ
Munshi
Sanjeev K
SK
Espeseth
Amy S
AS
Zuck
Paul
P
Colussi
Dennis
D
Wolfe
Abigail
A
Pietrak
Beth L
BL
Lai
Ming-Tain
MT
Vacca
Joseph P
JP
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D011485:Protein Binding; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D053829:Amyloid Precursor Protein Secretases