title: Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co, West Point, PA 19486, USA. shawn_stachel@merck.com
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Stachel
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.forename: Diane
authors.initials: D
authors.lastname: Rush
authors.forename: Kristen L G
authors.initials: KL
authors.lastname: Jones
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Hemaka
authors.initials: H
authors.lastname: Rajapakse
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Adam
authors.initials: A
authors.lastname: Simon
authors.forename: M
authors.initials: M
authors.lastname: Katharine Holloway
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Allison
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.forename: Paul
authors.initials: P
authors.lastname: Zuck
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Abigail
authors.initials: A
authors.lastname: Wolfe
authors.forename: Beth L
authors.initials: BL
authors.lastname: Pietrak
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D053829:Amyloid Precursor Protein Secretases