title: Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency.
abstract: The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA. Electronic address: melissaegbertson@gmail.com.
authors.forename: Melissa
authors.initials: M
authors.lastname: Egbertson
authors.affiliation: Structural Chemistry, WP53-3 Merck and Co., West Point, PA 19486, USA.
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.affiliation: NMR Structure Elucidation, Process and Analytical Chemistry, WP14-1 Merck and Co., West Point, PA 19486, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pitzenberger
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Stachel
authors.affiliation: Sunesis Pharmaceuticals, 395 Oyster Point Blvd. Ste. 400, South San Francisco, CA 94080, USA.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Yang
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: Lou Anne
authors.initials: LA
authors.lastname: Neilson
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: Melody
authors.initials: M
authors.lastname: McWherter
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Perlow
authors.affiliation: Sunesis Pharmaceuticals, 395 Oyster Point Blvd. Ste. 400, South San Francisco, CA 94080, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Fahr
authors.affiliation: Structural Biology, WP 14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.affiliation: Structural Biology, WP 14-2 Merck and Co., West Point, PA 19486, USA. Electronic address: timothy.j.allison@gmail.com.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Allison
authors.affiliation: Structural Chemistry, WP53-3 Merck and Co., West Point, PA 19486, USA.
authors.forename: Katharine
authors.initials: K
authors.lastname: Holloway
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA. Electronic address: selnickh@gmail.com.
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: ZhiQiang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Process Chemistry, WP 14-1 Merck and Co., West Point, PA 19486, USA.
authors.forename: John
authors.initials: J
authors.lastname: Swestock
authors.affiliation: Pharmacology, WP 26-1 Merck and Co., West Point, PA 19486, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.affiliation: Pharmacology, WP 26-1 Merck and Co., West Point, PA 19486, USA.
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.affiliation: Pharmacology, WP 26-1 Merck and Co., West Point, PA 19486, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.affiliation: Pharmacology, WP 26-1 Merck and Co., West Point, PA 19486, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Tugusheva
authors.affiliation: Pharmacology, WP 26-1 Merck and Co., West Point, PA 19486, USA.
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.affiliation: Pharmacology, WP 26-1 Merck and Co., West Point, PA 19486, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.affiliation: Pharmacology, WP 26-1 Merck and Co., West Point, PA 19486, USA.
authors.forename: Shari
authors.initials: S
authors.lastname: Haugabook
authors.affiliation: Drug Metabolism, WP 75-B Merck and Co., West Point, PA 19486, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.affiliation: Drug Metabolism, WP 75-B Merck and Co., West Point, PA 19486, USA.
authors.forename: I-W
authors.initials: IW
authors.lastname: Chen
authors.affiliation: Imaging Research, WP 44c Merck and Co., West Point, PA 19486, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Holahan
authors.affiliation: Imaging Research, WP 44c Merck and Co., West Point, PA 19486, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Stranieri-Michener
authors.affiliation: Imaging Research, WP 44c Merck and Co., West Point, PA 19486, USA.
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vacca
authors.affiliation: Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D006827:Hydantoins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Amyloid; Beta secretase; Magic methyl effect; Spiropiperidine